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In 2020 about 89,000 adolescents and young adults (AYA) (ages 15 to 39) were estimated to be diagnosed with cancer in the United States, 23,890 had CNS and spinal nervous system(SNS) involvement—accounting for one twentieth or five percent of the number cancer diagnoses in the United States. The estimated deaths for this group was18,020 deaths in 2020 (1).

Background: 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a poly-chlorinated pyridine cholesteryl carbonate that was designed to penetrate the blood brain barrier and be useful as therapy for brain tumors (IND 68,876). A 3-stage mechanism is proposed for drug entry into the CNS and into cancer cells via reversible binding with sialic acid on the surface of RBC’s; and transported into cancer cells with L-glutamine. DM-CHOC-PEN has a MOA via bis-alkylation of DNA @ N7-guanine and N4-cytosine. DM-CHOC-PEN has completed clinical trials involving sixty-four (64) adults and nineteen (19) adolescent/young adult subjects with advanced cancers. Long term survival, good qualities of life and minimal toxicities [AACR #1185, 2013; AACR #CT 129, 2019; AACR #CT152, 2021] have been reported. This update provides affirmation that the drug, previously described as a treatment for non-small cell lung cancer (NSCLC) involving the CNS, is well tolerated with continued durations of responses, no new toxicities, good survival and good quality of life. Primary aims of the previously reported DM-CHOC-PEN clinical trials were to assess clinical response and monitor toxicities/safety and verify the maximum tolerated doses (MTD) for the drug administered IV to subjects with cancer. Here is an update on the long term responses, tolerance and quality of survival in subjects with NSCLC involving the CNS. Subjects & Methods: DM-CHOC-PEN was administered to adults (> 18 y/o) with NSCLC involving the CNS that lacked genetic rearrangements or tumor targets and/or had failed standard therapies as a 3-hr IV infusion once every 21 days employing a verified 2-tiered MTD schedule: 85.8 mg/m2 for subjects with liver involvement and 98.7 mg/m2 for subjects with normal livers. Results: Sixteen (16) adult subjects with NSCLC have been treated to date, which 11 had NSCLC (adeno/large cell carcinomas) involving the CNS that lacked genetic rearrangements, had no tumor targets, and/or had failed standard therapies. Seven of the 11 subjects with NSCLC involving the CNS also possessed cerebellar metastases. The drug was well tolerated with no Gr-3 toxicities. The most common Gr-2 adverse effects were reversible fatigue (17%), reversible vasogenic edema (9%) and nausea (9%). No drug associated neuro/psychological, hematological, cardiac or renal toxicities have been observed, nor have there been any drug associated deaths reported. The pK modelling and properties for the drug have been previously reported [AACR #1185, 2013] and continue to be confirmed. Eight (8) subjects with NSCLC involving the CNS responded to DM-CHOC-PEN with documented CR/PR (RECIST 1.1) and improved OS/QOL/PFS (Kaplan-Meier) lasting 8 - 82+ mos. with survivals of 25% at 34 mos., 50% at 10 mos. and 8% at 84+ mos. Conclusion: DM-CHOC-PEN is a bis-alkylator of DNA that is safe at the dose levels described and has produced long term objective responses with manageable toxicities and improved quality of life in subjects with NSCLC involving the CNS lacking genetic rearrangements or tumor targets and/or had failed standard therapies. Complete data on subject responses and observed toxicities will be presented. Supported by NCI/SBIR grants - R43/44CA132257 and NIH NIGMS 1 U54 GM104940 - the latter supports the Louisiana Clinical and Translational Science Center, New Orleans, LA Citation Format: Lee Roy Morgan, Roy S. Weiner, T. Mahmood, C. Gordon, M. Bhandari, AH Rodgers, ML Ware, Marc Matrana, Thomas M. Cosgriff, Philip Friedlander, J-J Zou. Use of 4-demethyl-4-cholesteryloxycarbonyl-penclomedine (DM-CHOC-PEN) as therapy for advanced non-small cell lung cancer (NSCLC) involving the CNS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT158.

Background: 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a poly-chlorinated pyridine cholesteryl carbonate with a MOA via bis-alkylation of DNA @ N7-guanine and N4-cytosine that is currently in Phase II trial in AYA subjects with cancer that have CNS involvement. The aims for the trials are to assess clinical responses, monitor toxicities, safety and confirm the MTDs for IV administered DM-CHOC-PEN (IND 68,876) to AYA subjects with cancer involving the CNS. We report here responses and toxicities observed to date in Phases I & II DM-CHOC-PEN clinical trials with AYA subjects that had cancer involving the CNS. Subjects & Methods: DM-CHOC-PEN was administered as a 3-hr IV infusion once every 21 days to AYA subjects. The dosing schedule was 2-tiered: subjects with liver involvement received 85.8 mg/m2 and subjects with normal liver function received 98.7 mg/m2. Results: nineteen (19) AYA subjects with CNS involvement have been treated to date. The common tumor types treated were oligoastrocytoma, astrocytoma, GBM; leukemia (ALL), lymphoma (NHL), melanoma, breast and lung cancers (NSCL). Three (3) AYA patients are currently being followed with diagnoses of breast cancer, astrocytoma, and lung cancer and have had good qualities of life at 12, 59 and 72+ mos. All patients have been followed with lab tests, scans (RECIST 1.1) and virtual exams. The drug was well tolerated. The most common adverse effect was fatigue (17%). No neuro/cognitive, liver dysfunction, hematological, cardiac, renal or GI toxicities were observed. PK modeling revealed that AUCs were parallel for all dose levels. The Cmax for DM-CHOC-PEN and DM-PEN (4-demethylpenclomedine, a metabolite) were 3 and 24 hours, respectively for the AYA subjects; similar to what was seen for older adults. The drug and metabolite were still detectable in plasma and rbcs for 21 to 50 days in the AYA (15 – 39 y/o) group vs. 3 to < 21 days (previously reported for adult subjects (>60 y/o) (AACR #1185, 2013). Differences in PK profiles between AYA and older adult subjects will also be reviewed in depth. Conclusion: DM-CHOC-PEN is safe for usage and has produced objective responses with manageable toxicities in AYA subjects with cancer involving the CNS. Complete data on subject responses and observed toxicities will be presented. We propose a 3-stage mechanism for drug entry into the CNS and into cancer cells via reversible binding with RBCs and then association with L-glutamine transport into cells. Supported by NCI/SBIR grants – R43/44CA132257 and R43CA203351 and NIH NIGMS 1 U54 GM104940. Citation Format: Lee Roy Morgan, Roy S. Weiner, Tallat Mahmood, Marcus L. Ware, Andrew H. Rodgers, Manish Bhandari, Philip Friendlander. Early phase II clinical trial results for 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) in adolescents and young adults (AYA) with brain cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P038.

Background: 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a poly-chlorinated pyridine cholesteryl carbonate with a MOA via bis-alkylation of DNA @ N7-guanine and N4-cytosine that has completed Phase I and II trials (the latter including subjects with CNS involvement) [AACR #1185, 2013; AACR #CT 129, 2019]. The primary aims of the previously reported Phase I/II DM-CHOC-PEN trials were to assess clinical response and monitor toxicities/safety and verify the maximum tolerated doses (MTD) for IV administered DM-CHOC-PEN (IND 68,876) to subjects with cancer. We report here the responses and toxicities seen in subjects with NSCLC involving the CNS that lacked genetic rearrangements, tumor targets and/or had failed standard therapies. Subjects & Methods: DM-CHOC-PEN was administered to adults (> 18 y/o) as a 3-hr IV infusion once every 21 days employing a verified 2-tiered MTD schedule: 85.8 mg/m2 for subjects with liver involvement and 98.7 mg/m2 for subjects with normal livers. Results: Fifty two (52) adult subjects with cancer have been treated to date, including16 subjects with lung cancer, of which 11 had NSCLC (adeno/large cell carcinomas) involving the CNS that lacked genetic rearrangements/no tumor targets and/or had failed standard therapies. Seven of the 11 subjects with NSCLC involving the CNS also possessed cerebellar metastases. The drug was well tolerated; the most common adverse effects were fatigue (17%), reversible liver dysfunction (9%) and nausea (11%). No neuro/psychological, hematological, cardiac or renal toxicities were observed, nor drug associated deaths. PK modeling revealed that AUCs were parallel for both the 85.8 and 98.7 mg/m2 doses employed. The Cmax for DM-CHOC-PEN and DM-PEN (4-demethylpenclomedine, a metabolite) at the MTD were 3 and 24 hours, respectively. Both DM-CHOC-PEN and DM-PEN were detected for up to 15 days post administration associated with rbc's. DM-CHOC-PEN was also detected in CNS tumor tissue obtained anatomically from five (5) subjects - in concentrations of 75-210 ng/g, 22 days to 9 mos. post-treatments. 8 subjects have responded with CR/PR (RECIST 1.1) and improved OS/QOL/PFS (Kaplan-Meier) lasting 8+ - 70+ mos. Conclusion: DM-CHOC-PEN is a bis-alkylator of DNA that is safe at the dose levels described and has produced long term objective responses with manageable toxicities in subjects with NSCLC involving the CNS lacking genetic rearrangements or tumor targets and/or had failed standard therapies. Complete data on subject responses and observed toxicities will be presented. A 3-stage mechanism is proposed for drug entry into the CNS and into NSCLC cells via reversible binding with RBC's and then associated with L-glutamine transport into cells. Supported by NCI/SBIR grants - R43/44CA132257 and NIH NIGMS 1 U54 GM104940 - the latter funds from the Louisiana Clinical and Translational Science Center, New Orleans, LA. Citation Format: Roy S. Weiner, Lee Roy Morgan, Marcus Ware, Tallat Mahmood, Craig Gordon, Manish Bhandari, Andrew Rodgers, Marc Matrana, Thomas M. Cosgriff, Philip Friedlander, Jay J. Zou. Phase II clinical trial results for 4-demethyl-4-cholesteryloxycarbonyl-penclomedine (DM-CHOC-PEN) in advanced non-small cell lung cancer (NSCLC) involving the CNS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT152.

T lymphocytes play a central role in many human immunologic disorders, including autoimmune and alloimmune diseases. In hematopoietic stem cell transplantation, acute graft-versus-host-disease (GVHD) is caused by an attack on the recipient’s tissues from donor allogeneic T cells. Selectively depleting GVHD-causing cells prior to transplant may prevent GVHD. In this study, we evaluated 24 chalcogenorhodamine photosensitizers for their ability to selectively deplete reactive T lymphocytes and identified the photosensitizer 2-Se-Cl, which accumulates in stimulated T cells in proportion to oxidative phosphorylation. The photosensitizer is also a potent stimulator of P-glycoprotein (P-gp). Enhanced P-gp activity promotes the efficient removal of photosensitizer not sequestered in mitochondria and protects resting lymphocytes that are essential for antipathogen and antitumor responses. To evaluate the selective depletion of alloimmune responses, donor C57BL/6 splenocytes were cocultured for 5 d with irradiated BALB/c splenocytes and then photodepleted (PD). PD-treated splenocytes were infused into lethally irradiated BALB/c (same-party) or C3H/HeJ (third-party) mice. Same-party mice that received PD-treated splenocytes at the time of transplant lived 100 d without evidence of GVHD. In contrast, all mice that received untreated primed splenocytes and third-party mice that received PD-treated splenocytes died of lethal GVHD. To evaluate the preservation of antiviral immune responses, acute lymphocytic choriomeningitis virus infection was used. After photodepletion, expansion of Ag-specific naive CD8+ T cells and viral clearance remained fully intact. The high selectivity of this novel photosensitizer may have broad applications and provide alternative treatment options for patients with T lymphocyte–mediated diseases.

Purpose: 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a poly-chlorinated pyridine cholesteryl carbonate with a MOA via bis-alkylation of DNA @ N7-guanine and N4-cytosine that has completed Phase I/II studies [AACR, #CT129, 2017] in adult subjects with cancers involving the CNS. Four (4) subjects in the Phase I/II trials required surgery for persistent CNS lesions following DM-CHOC-PEN therapy with 39-98.8 mg/m2 of drug. DM-CHOC-PEN was identified in samples from all 4-subjects - 90-212 ng/g tumor. Thus, the drug penetrates the CNS and tumors and is available to act as a radiosensitizer; the latter has been supported with in vitro studies [AACR, #4746, 2017]. The current presentation reviews the long term Phase I clinical data that supports safety, dose-tolerance and use of DM-CHOC-PEN plus radiation in subjects with cancers involving the CNS - IND 68,876. Patients & Methods: DM-CHOC-PEN was administered as a 3-hr IV infusion once to subjects with advanced cancer involving the CNS. A single dose (39 mg/m2 to 98.7 mg/m2 in escalating Phase I scheme) was administered once anywhere from 48 hours to 3-weeks prior to receiving stereotactic radiosurgery (SRS) or whole brain radiation therapy (WBRT). Radiation was administered in doses of 15-30 Gy depending on the size and number of lesions. Results: Nineteen (19) subjects with cancer involving the CNS have been treated to date with DM-CHOC-PEN (6-NSCLC, 1-breast, 1-melanoma, 5-GBM, 3-sarcomas, 1-astrocytoma & 2-renal cell carcinomas). Subjects received 39, 50, 70, 86.8 or 98.7 mg/m2 of DM-CHOC-PEN. Five subjects received WBRT (30 Gy) and 14 subjects received SRS (15-24 Gy. One (1) subject with NSCLC did develop vasogenic edema and tumor necrosis which resolved and the subject is in complete remission 55+ mos. A second subject with a recurrent GBM developed Gr-3 confusion secondary to an enlarging lesion which was removed. Drug was present in ng/g of tumor conc.; confusion resolved. Ten (10) of the thirteen (13) subjects have had objective results (OS 8-58 mos.) Bioavailability for DM-CHOC-PEN revealed a rebound phenomenon @ ~ 50 hours post-infusion with a T-release of 26.7 h. and drug in the plasma (Cmax=17.5 µg/mL) until day 15 . The AUC was linear for all doses. Pre-clinical radiosensitization in vitro studies [AACR #1917, 2017] supported the present trial. Photon induced charge transfer reactions with DM-CHOC-PEN will be discussed as a MOA. Conclusion: Data is presented that documents effectiveness and safety of DM-CHOC-PEN plus radiation as therapy for subjects with cancers involving the CNS. Observations during this trial supported the drug's ability to penetrate human tumors involving the CNS and acceptability as a method to improving responses to radiation. Complete data on subject responses and observed toxicities will be presented. Supported by - NCI/SBIR grants - R43 CA213545-02 and NIH NIGMS 1 U54 GM104940 - the latter funds the Louisiana Clinical and Translational Science Center. Citation Format: Steven J. DiBiase, Roy S. Weiner, Tallat Mahmood, Kendra Harris, Ronald Kawauchi, Kiran Devisetty, James Herman, Manish Bhandari, Marcus Ware, Paul Friedlander, Lee R. Morgan, Ali Baghian. Phase I clinical trial: results from the use of 4-demethyl-4 cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) plus radiation as treatment for cancers involving the CNS [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT101.

Background: 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a poly-chlorinated pyridine cholesteryl carbonate with a MOA via bis-alkylation of DNA @ N7-guanine and N4-cytosine that has completed Phase I and now in Phase II clinical trials in AYA subjects with cancer with CNS involvement. The aims were to assess clinical responses, monitor toxicities/safety and confirm MTDs for IV administered DM-CHOC-PEN in AYA individuals (IND 68,876). We report here responses, pharmacokinetics and toxicities seen in Phase I/II DM-CHOC-PEN trials with AYA subjects +/- CNS involvement. Subjects & Methods: DM-CHOC-PEN was administered as a 3-hr IV infusion once every 21 days to subjects with advanced cancer in escalating doses from 50 to 98.7 mg/m2. The MTD identified was similar to that seen during the adult Phase I trial – 85.8 mg/m2 for subjects with liver involvement and 98.7 mg/m2 for subjects with normal liver function. Results: Fifteen (15) AYA subjects have been treated to date (with or without CNS involvement). The common tumor types treated were oligoastrocytoma, astrocytoma, GBM; leukemia (ALL), lymphoma (NHL), melanoma, breast and lung cancers (NSCL). Most subjects (12) had CNS involvement. The drug was well tolerated; the most common adverse effects were fatigue (17%). No neuro/cognitive, liver dysfunction, hematological, cardiac, renal or GI toxicities were observed. PK modeling revealed that AUCs were parallel for all dose levels (50-98.7 mg/m2). The Cmax for DM-CHOC-PEN was 100 hours for the AYA subjects; very different to what has been observed for older adults (>50 y/o). The drug was also cleared quicker, as compared to older adults (2o to less existing co-morbidities in the AYA subjects). However, the drug was detectable in plasma and rbcs for 15 days in the AYA (15 – 39 y/o). Differences in PK profiles between AYA and older adult subjects will be reviewed in depth. Three (3) of the AYA subjects (1 each with NSCLC, astrocytoma and breast cancers involving the CNS) have responded with CR/PR (RECIST 1.1), improved QOL/PFS (Kaplan-Meier) and OS from 12 to 58+ mos. All subjects will be reviewed. Conclusion: DM-CHOC-PEN is safe in doses of 39 – 98.7 mg/m2 and has produced objective responses with manageable toxicities in AYA subjects with cancer involving the CNS. Complete data on subject responses and observed toxicities will be presented. We propose a 3-stage mechanism for drug entry into the CNS and into cancer cells via reversible binding with RBCs and then association with L-glutamine transport into cells. Supported by NCI/SBIR & LA state grants – R43/44CA132257, R43/44CA203351 and NIH NIGMS 1 U54 GM104940 – the latter funds the Louisiana Clinical and Translational Science Center. Citation Format: Lee Roy Morgan, Roy S. Weiner, Tallat Mahmood, Marcus Ware, Andrew H. Rodgers, Manish Bhandari, Philip Friedlander. Phase I/II clinical trial results for 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) as treatment for adolescents and young adults (AYA) with cancers involving the CNS [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT181.

The authors describe the case of a patient who initially presented with uterine leiomyosarcoma (LMS) that later metastasized to the spine. The patient was treated at another institution for her primary uterine LMS, undergoing resection followed by adjuvant chemotherapy. After several years of disease remission, the patient presented in January 2011 to the authors’ institution with recurrent uterine LMS metastatic to the spine, which has been treated with multiple therapeutic modalities in a combination of surgery, radiosurgery, and chemotherapy. As a result of this approach, the patient has been progression free for 35 months since her presentation (April 2011 to March 2014). We herein describe our experience treating this patient with recurrent uterine LMS of the spine and suggest that patients with recurrent uterine LMSs should be considered for treatment using a multimodality approach with emphasis on enrollment into clinical trials.

Background and Objectives Since a study published in 2002 showed a survival advantage of melphalan-only conditioning for stem cell transplantation (HSCT) over melphalan-total body irradiation (mel-TBI) in patients with multiple myeloma (MM), most centers abandoned mel-TBI. Mel-TBI causes more early toxicity and is more complicated to administer, but we speculated it may result in longer term survival with radiation as an independent treatment modality. Therefore, we analyzed the long-term outcome of patients with MM who received mel-TBI as part of conditioning at our center. Patients and Methods From 1995–2013, 50 patients with MM underwent autologous HSCT at Tulane University Medical Center using mel-TBI conditioning. We used Kaplan-Meier survival analysis and compared our patients with data available from the Louisiana Tumor Registry. Results The mean survival of our patients was 70.98 months from time of transplant and 84.2 months from time of initial diagnosis. No differences were observed according to gender, ethnicity, or age at transplant. The expected median survival in a population-based registry (matched for age and year of treatment) was 27 months (p

Background: 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a poly-chlorinated pyridine cholesteryl carbonate with a MOA via bis-alkylation of DNA @ N7-guanine and N4-cytosine. DM-CHOC-PEN has completed Phase I/II studies as a single agent and as a radiosensitizer in subjects with cancers involving the CNS [AACR #CT129, 2016; CT069, 2019]. The current presentation reviews in vitro data that support DM-CHOC-PEN’s ability to under go polarization in a magnetic field with enhanced release in situ of the active alkylating specie – demethylpenclomedine (DM-PEN) improving cell kill – a potential enhancer for cancer management. Methods: Human non-small cell lung cancer (NSCLC) adenocarcinoma cells (H-2086) were obtained from ATCC (Manassas, VA) and maintained in tissue culture – 1640 RPMI with L-glutamine plus 10% FBS and 5% antibiotic-antimycotic solution (Sigma) in a moist 5% CO2 atmosphere @ 37oC. NSCLC cell cultures (106 cells/mL) in plates (5 cm dia.) were exposed for 24-72 hrs. to magnets (MagnetTM) that generated magnetic field strengths of 85 -110 mT. The plated cultures were treated with DM-CHOC-PEN (0.25, 0.4 & 1.0 µg/mL) +/- magnetic field exposure and monitored for cell survival and growth characteristics. Results: The in vitro studies revealed: DM-CHOC-PEN (0.25 µg/mL) alone produced an IC35 vs. NSCLC cells, while a magnetic field force (110 mT) alone had no effect on cell growth. In combination - DM-CHOC-PEN (0.25 µg/mL) plus a magnetic field force (110 mT) added 48 hrs post-drug exposure produced a cell kill of 100%. Thus, in combination – drug (0.25 µg/mL) plus a magnetic field force of 110 mT – improved the therapeutic effort, as compared to either treatment alone. Release of DM-PEN was quantitated in the culture medium +/- magnetic field exposure. Drug dose exposure vs. responses will be discussed.Conclusion: DM-CHOC-PEN is polarized in a magnetic field with shifting of electron flux toward the polychlorinated pyridine ring and weakening the carbonate link facilitating its reactivity with H2O (hydrolysis) and the loss of the cholesteryl carbonate moiety, resulting in the release of the active specie – DM-PEN. DM-PEN is involved in DM-CHOC-PEN’s second phase of DNA alkylation. Thus, the ‘controlled release’ of the active specie in magnetic fields potentiates cytotoxicity and ultimately may reduce the amount of drug required for effective anti-cancer activity. Supported by – NCI/SBIR grants - R43/44CA132257 and NIH NIGMS 1 U54 GM104940 – the latter funds the Louisiana Clinical and Translational Science Center. Citation Format: Lee Roy Morgan, Ryen Smith, Branko Jursic, Roy S Weiner, Andrew H Rodgers. Support for 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) as a magnetic field effort sensitizer in NSCLC [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A098. doi:10.1158/1535-7163.TARG-19-A098

Purpose:4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a poly-chlorinated pyridine cholesteryl carbonate with a mechanism of action (MOA) via bis-alkylation of DNA @ N7-guanine and N4-cytosine that has completed Phase I/II studies [AACR, 58, #CT129, 2017] in subjects with cancers involving the CNS. Four (4) subjects in the Phase I/II trials required surgery for persistent CNS lesions following DM-CHOC-PEN therapy and DM-CHOC-PEN was identified in samples from all 4-subjects - 90-212 ng/g tumor [subjects had been treated with 39-98.8 mg/m2 of drug]. Thus, the drug penetrates the CNS and concentrates in tumors. It is available, therefore, to act as a radiosensitizer as demonstrated in in vitro studies [AACR, 58, #4746, 2017]. The current presentation reviews Phase I clinical data that supports the safety, dose-tolerance, and use of DM-CHOC-PEN with radiation in subjects with cancers involving the CNS - IND 68,876. Patients & Methods: DM-CHOC-PEN was administered as a 3-hr IV infusion once every 21 days to subjects with advanced cancer involving the CNS. A single dose was administered prior to standard radiation therapy. The dose was escalated from 39 mg/m2 to 98.7 mg/m2 I.X1, then 3-weeks later the subject received stereotaxic radio-surgery (SRS) or whole brain irradiation (WBRT). Total radiation administered was 15-30 Gy depending on the size and number of lesions. Results: Nine (9) subjects with cancer involving the CNS have been treated to date - (6-NSCLC, 1-breast, 1-melanoma & 1-sarcoma). Subjects received 39, 55, 70, 86.8 or 98.7 mg/m2 followed by 15-30 Gy of radiation. The drug/radiation combination was well tolerated. One (1) subject with NSCLC developed vasogenic edema and tumor necrosis which resolved; that subject is in complete remission 31+ mos. Six out of nine subjects have had objective responses (OS 4 - 42+ mos.) Bioavailability for DM-CHOC-PEN revealed a rebound phenomenon @ ~ 50 hours post-infusion with a T-release of 26.7 h. The same phenomenon was observed with RBCs (estimation using Monolix 3.2). DM-CHOC-PEN was detected bound to RBCs for 3-days (after 70 mg/m2); DM-CHOC-PEN was also detected in the urine (Cmax=17.5 µg/mL) until day 15. The AUC was linear for all doses. Pre-clinical in vitro studies supported the clinical data: NSCLC cells treated with DM-CHOC-PEN (0.1 -1.0 µg/mL) demonstrated 50 & 100% cytotoxicity @ 0.4 & 1.0 µg/mL. For radiation alone (6, 9 &12 Gy) - cell kill was 20 & 65% @ 6 & 12 Gy [100% kill was not observed at this dose range]; for DM-CHOC-PEN (0.25 µg/mL) plus radiation (6-12 Gy) - cell kill was 80 & 100% @ 6 & 12 Gy. Photon induced charge transfer reactions with DM-CHOC-PEN will be discussed. Conclusion: Preliminary data is presented that supports enhanced cytotoxicity and safety of DM-CHOC-PEN plus radiation as therapy for subjects with cancers involving the CNS. Observations during Phase I/II clinical trials with DM-CHOC-PEN alone support the drug's persistent presence in human tumors after systemic administration and possible positive effects on response to subsequent radiation. Complete data on subject responses and observed toxicities will be presented. Supported by - NCI/SBIR grants - R43 CA213545-01 and NIH NIGMS 1 U54 GM104940 - the latter funds the Louisiana Clinical and Translational Science Center. Citation Format: LR Morgan, T Mahmood, R S. Weiner, R Kawauchi, M Bhandari, K Devisitty, J Herman, R Summe, ML Ware, P Friedlander, AH Rodgers. Early phase I clinical trial results for 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) plus radiation in cancers involving the CNS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT119.

The optimal dose of weekly docetaxel in combination with cisplatin and concomitant thoracic radiation therapy (XRT) in patients with locally advanced non-small cell lung cancer (NSCLC) is not well defined. The purpose of this study was to define the maximal tolerated dose (MTD) of docetaxel in this combination. Eligible patients had unresectable stage IIIA or IIIB NSCLC without pleural effusion. Treatment consisted of cisplatin 25 mg/m(2) plus docetaxel weekly and concomitant standard XRT for a total of 60 Gy at 200 cGy/fraction/day 5 times weekly for 6 weeks. The starting dose of docetaxel in the first cohort was 15 mg/m(2)/week. This dose was escalated by 5 mg/m(2) per cohort of 3 patients. No intrapatient dose escalation was allowed. The doses of cisplatin and XRT were not escalated. A total of 23 patients were enrolled, and 19 patients were evaluable for analysis. The first cohort (docetaxel 15 mg/m(2)/week) completed treatment without any Grade 3 or 4 toxicities. The second cohort (docetaxel 20 mg/m(2)/week) was expanded to 6 patients because of Grade 3 cough observed in 1 patient. One of 5 patients experienced Grade 3 esophagitis at the docetaxel 25 mg/m(2)/week dose level. Dose limiting toxicity consisting of Grade 3 esophagitis was reached in 4 of 5 patients receiving docetaxel at 30 mg/m(2)/week. This study determined the MTD of weekly docetaxel to be 25 mg/m(2) when combined with cisplatin 25 mg/m(2) and radiation therapy for locally advanced NSCLC. Further evaluation of this regimen in a phase II trial is underway.

Background: 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a poly-chlorinated pyridine cholesteryl carbonate with a MOA via bis-alkylation of DNA @ N7-guanine and N4-cytosine that has completed phase I and II trials in adult subjects with cancer that had +/- CNS involvement (AACR #1185, 2013; AACR #CT 129, 2017). The aims were to assess clinical responses, monitor toxicities/safety, and confirm MTDs for IV administered DM-CHOC-PEN (IND 68,876). We report here responses and toxicities seen in a phase I DM-CHOC-PEN trial with AYA subjects who have cancer (some of whom had CNS involvement). Subjects and Methods: DM-CHOC-PEN was administered as a 3-hr IV infusion once every 21 days to subjects with advanced cancer in escalating doses from 39 - 98.7 mg/m2. The dosing schedule accounted for the liver toxicities seen in the adult phase I trial and was 2-tiered: for subjects with liver involvement, the cutoff was 85.8 mg/m2 and for subjects with normal liver function was 98.7 mg/m2. Results: Twelve (12) AYA subjects have been treated to date (with or without CNS involvement). The common tumor types treated were oligoastrocytoma, astrocytoma, GBM; leukemia (ALL), lymphoma (NHL), melanoma, breast, and lung cancers (NSCL). Most subjects (9) had CNS involvement. The drug was well tolerated; the most common adverse effects were fatigue (17%). No neuro/cognitive, liver dysfunction, hematologic, cardiac, renal, or GI toxicities were observed. PK modeling revealed that AUCs were parallel for all dose levels (39-98.7 mg/m2). The Cmax for DM-CHOC-PEN and DM-PEN (4-demethylpenclomedine, a metabolite) were 3 and 24 hours, respectively for the AYA subjects, similar to what was seen for older adults. However, the drug and metabolite were still detectable in plasma and rbcs for 21 to 50 days in the AYA (15 - 39 yo) group vs. 3 to < 21 days (as observed in previously treated adult (>60 yo) subjects (AACR #1185, 2013). Differences in PK profiles between AYA and older adult subjects will be reviewed in depth. Three (3) of the AYA subjects (1 each with NSCLC, ALL, and astrocytoma involving the CNS) have responded with CR/PR (RECIST 1.1), improved QOL/PFS (Kaplan-Meier), and OS from 8 to 26+ mos. All subjects will be reviewed. Conclusion: DM-CHOC-PEN is safe in doses of 39 - 98.7 mg/m2 and has produced objective responses with manageable toxicities in AYA subjects with cancer involving the CNS. Complete data on subject responses and observed toxicities will be presented. We propose a 3-stage mechanism for drug entry into the CNS and into cancer cells via reversible binding with RBCs and then association with L-glutamine transport into cells. Supported by NCI/SBIR grants - R43/44CA132257 and R43CA203351A and NIH NIGMS 1 U54 GM104940. Citation Format: Lee Roy Morgan, Andrew H. Rodgers, Roy S. Weiner, Tallat Mahmood, Marcus L. Ware, Manish Bhandari, Philip Friedlander. Early clinical trial results for 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) in adolescents and young adults (AYA) with cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A086.

Background: 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a poly-chlorinated pyridine cholesteryl carbonate with a MOA via bis-alkylation of DNA @ N7-guanine and N4-cytosine that has completed Phase I and II trials (the latter on subjects with CNS involvement) [AACR #1185, 2013; AACR #CT 129]. The primary aim was to assess clinical response and secondary aims to monitor toxicities/safety and verify the MTDs for IV administered DM-CHOC-PEN that derived in Phase I study (IND 68,876). We report here the responses and toxicities seen in all the subjects treated. Subjects & Methods: In Phase I, DM-CHOC-PEN was administered as a 3-hr IV infusion once every 21 days to subjects with advanced cancer; cohorts received escalating doses from 39 - 111 mg/m2. The Phase II dose schedule was 2-tiered: 85.8 mg/m2 for subjects with liver involvement and 98.7 mg/m2 for subjects with normal livers. Results: Fifty two (52) subjects have been treated to date - 25 in Phase I (cancer subjects with or without CNS involvement) and 27 in Phase II (with CNS involvement). The common tumor types treated were primary brain cancers and melanoma, breast, and lung cancers involving the CNS. The drug was well tolerated; the most common adverse effects were fatigue (17%), reversible liver dysfunction (9%) and nausea (11%). No neuro/psychological, hematological, cardiac or renal toxicities were observed. PK modeling revealed that AUCs were parallel for all dose levels (39-111 mg/m2). The Cmax for DM-CHOC-PEN and DM-PEN (4-demethylpenclomedine, a metabolite) were 3 and 24 hours, respectively. Both DM-CHOC-PEN and DM-PEN were detected 3 to 15 days after administration associated (up to 50%) with rbcs. Of interest, young adults ( Citation Format: Roy S. Weiner, Lee Roy Morgan, T Mahmood, R. Kawauchi, C. Gordon, ML Ware, M. Matrana, TM Cosgriff, AH Rodgers, G. Bastian, M. Bhandari, J-J Zou. Clinical trial results for 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) in cancers involving the CNS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT052. doi:10.1158/1538-7445.AM2017-CT052

Background: 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a poly-chlorinated pyridine cholesteryl carbonate with a MOA via bis-alkylation of DNA @ N7-guanine and N4-cytosine that has completed Phase I/II studies [AACR #CT129, 2016] in subjects with cancers involving the CNS. The current presentation reviews clinical and in vitro data that support radiosensitizing properties for DM-CHOC-PEN in cancers involving the CNS. Patients & Methods: DM-CHOC-PEN was administered as a 3-hr IV infusion once every 21 days to subjects with advanced cancer involving the CNS. The dose schedule was 2-tiered: 85.8 mg/m2 for subjects with liver involvement and 98.7 mg/m2 for subjects with normal livers. All subjects with resistant or new CNS lesions that did not respond to DM-CHOC-PEN were given the option of surgery, stereotaxic radio-surgery (SRS) or whole brain irradiation (WBRT). As preclinical support, human NSCLC adenocarcinoma cells (H-2086) growing in culture (106 cells/mL) were pretreated with DM-CHOC-PEN (0.1 -1.0 µg/mL) for 24 hrs, drug washed, re-fed fresh medium and then 48 h later irradiated (SRS with 6, 9 or 12 Gy). Results: Fifty-three (53) subjects with/without CNS involvement have been treated to date with DM-CHOC-PEN. Five (5) subjects (4-NSCLC & 1-sarcomas) in the Phase I/II trials required surgery for persistent CNS lesions following DM-CHOC-PEN therapy. DM-CHOC-PEN was identified in samples from all subjects - 90-212 ng/g tumor [subjects had been treated with 39-98.8 mg/m2 of drug]. Five subjects (1-sarcoma & 4-NSCLC) who had been treated with DM-CHOC-PEN for 6-wks - 8-mos had persistent NSCLC lesions involving the CNS were treated with SRS or WBRT. All five subjects had excellent objective results (OS 8+ - 29+ mos) with no CNS toxicity. Preclinical in vitro studies supported the clinical data: NSCLC cells treated with DM-CHOC-PEN (0.1 -1.0 µg/mL) demonstrated 50 & 100% cytotoxicity @ 0.4 & 1.0 µg/mL; for SRS alone (6, 9 &12 Gy) - cell kill was 20 & 65% @ 6 & 12 Gy [100% kill was not observed at this dose range]; for DM-CHOC-PEN (0.25 µg/mL) + SRS (6-12 Gy) - cell kill was 80 & 100% @ 6 & 12 Gy. Thus, in combination - less drug (0.25 µg/mL) and 12 Gy - produced a 100% cell kill, as compared to either SRS or drug, alone. Photon induced charge transfer reactions with DM-CHOC-PEN will be discussed. Conclusion: Preliminary data is presented that supports DM-CHOC-PEN’s cytotoxicity and radiosensitizing properties in cancers involving the CNS. Observations during clinical trials support the drug’s persistent presence in human tumors after systemic administration and notable positive effect on response to subsequent radiation. Complete data on patient responses and observed toxicities will be presented. Supported by - NCI/SBIR grants - R43/44CA132257 and NIH NIGMS 1 U54 GM104940 - the latter funds the Louisiana Clinical and Translational Science Center. Citation Format: Lee Roy Morgan, R S. Weiner, T Mahmood, R. Kawauchi, K Devisetty, J Herman, M Bhandari, R Summe, E Benes, AH Rodgers, ML Ware, JS Hayman, J Weber, Jay J. Zou. Early clinical support for 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) as a radiosensitizer in cancers involving the CNS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4746. doi:10.1158/1538-7445.AM2017-4746

The purpose of this study was to determine the quality of peripheral blood progenitor cells (PBPC) collected after an initial autologous PBPC transplant. Tandem autologous transplants have been used in the treatment of several malignancies. Routinely, PBPC have been collected prior to the first transplant and used for both transplants. In the current study, PBPC harvested prior to the first high-dose therapy (HDT) were used as a source of progenitors for transplant 1, and a combination of bone marrow harvested prior to the first course of HDT and PBPC collected approximately 85 days after the first transplant were used to support the second HDT. We analyzed the quality of the PBPC collected 85-120 days after HDT and autologous PBPC transplant. CD34 and colony-forming units granulocyte-macrophage (CFU-GM) contents of those collections were poor, and hematopoietic recovery was more consistent with recovery from a bone marrow transplant than a PBPC transplant. Thirteen of 15 patients received both transplants. Days to absolute granulocyte count of 500 was 10 +/- 1.5 for the first transplant and 13.3 +/- 3.7 for the second (p < 0.01). The number of days to platelet count of 20,000 was 14.3 +/- 10.7 for the first transplant and 18 +/- 7 for the second transplant (p = 0.066). The number of days of total parenteral nutrition (TPN) and intravenous morphine used by patients for the first and second transplants was similar, whereas the length of hospitalization was 21.8 +/- 3.6 for the first transplant and 27.6 +/- 7.8 for the second transplant (NS). In conclusion, it appears that the quality of PBPC collected following a previous PBPC transplant may be compromised.

In 1996, Congress recognized a need to increase investigator initiated clinical research in American medical schools and provided funding through the National Institutes of Health (NIH) for clinical research curriculum development beginning in 1999. Teaching ethics has been integral to the clinical research curriculum. The content of ethics training in the NIH-funded curriculum at Tulane University School of Medicine has evolved from “learning” the regulatory aspects of the clinical research process to understanding the basis for the regulations and developing the sustained vigilance that may prevent a repetition of past atrocities perpetrated in the name of science and medicine. The “instrument of change” at Tulane was the US Holocaust Museum’s exhibit, Deadly Medicine: Creating the Master Race, which visited the WWII Museum in New Orleans from July 25 through October 15 of 2012. The exhibit, along with a rich agenda of outstanding lectures that accompanied it, altered the curriculum, not only for students in the masters programs but also for the spectrum of students in academic medical centers in New Orleans. The clinical research curriculum now focuses on the “unthinkable” experiments carried out to implement eugenics in Nazi Europe as well as the deceptions and atrocities carried out by American scientists more recently. The curriculum challenges students to recognize and resist the opportunities for new atrocities afforded by new technologies.

The applications of bone marrow transplantation for the management of advanced local disease are examined. This review for stage III and inflammatory carcinoma suggests enhanced effectiveness and a progressive decrease in costs for bone marrow transplantation.

Background: 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a poly-chlorinated pyridine cholesteryl carbonate with a MOA via bis-alkylation of DNA @ N7-guanine and N4-cytosine that has completed a Phase I study [AACR #1185, 2013] and is being evaluated in a Phase II trial in patients with primary brain cancers and with melanoma, breast, and lung cancers with metastases to brain. The aims are to assess clinical response when DM-CHOC-PEN is administered I.V. at MTD and to monitor duration of responses and safety (IND 68,876). We report here the responses and toxicities seen in patients with NSCLC involving the CNS. Patients & Methods: In Phase I, DM-CHOC-PEN was administered as a 3-hr IV infusion once every 21 days to patients with advanced cancer; cohorts received escalating doses from 39 - 111 mg/m2. The Phase II dose schedule is 2-tiered: 85.8 mg/m2 for patients with liver involvement and 98.7 mg/m2 for patients with normal livers. Results: Fifty two (52) patients have been treated to date - 26 in Phase I (cancer patients with or without CNS involvement) and 26 in Phase II (with CNS involvement). The drug was well tolerated; the most common adverse effects were fatigue (17%), reversible liver dysfunction (9%) and nausea (11%). No neuro/psychological, hematological, cardiac or renal toxicities were observed. PK modeling revealed that AUCs were parallel for all dose levels (39-111 mg/m2). The Cmax for DM-CHOC-PEN and DM-PEN (4-demethylpenclomedine, a metabolite) were 3 and 24 hours, respectively. Both DM-CHOC-PEN and DM-PEN were detected 3 to 15 days after administration associated (up to 50%) with rbcs. DM-CHOC-PEN was also detected in CNS tumor tissue obtained surgically from five (5) patients - concentrations of 75-210 ng/g, 22 days to 9 mos. post treatments at doses of 39 or 98.7 mg/m2 of drug. To date, 16 patients with lung cancer (11 with NSCLC involving the CNS) have been treated. Seven of the 11 patients with NSCLC involving the CNS (incl. 6 with cerebellar disease) have responded with CR/PR (RECIST 1.1) and improved OS/QOL/PFS (Kaplan-Meier) lasting 6+ - 21+ mos. Conclusion: DM-CHOC-PEN is safe at these dose levels and has produced objective responses with manageable toxicities in NSCLC involving the CNS. Complete data on patient responses and observed toxicities will be presented. We propose a 2-stage mechanism for drug entry into the CNS and into NSCLC cells via reversible binding with RBCs and then L-glutamine transport into cells. Supported by NCI/SBIR grants - R43/44CA132257 and NIH NIGMS 1 U54 GM104940 - the latter funds the Louisiana Clinical and Translational Science Center. Citation Format: Roy S. Weiner, T Mahmood, C Gordon, ML Ware, LR Morgan, TM Cosgriff, AH Rodgers, G Bastian, R Kawauchi, M Matrana, J-J Zou. Phase II clinical trial results for 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) in NSCLC involving the CNS. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT129.

Taking care of palliative care patients and breaking bad news to them will never be an easy task. Excellent communication skills are essential while taking care of patients who face a life-threatening disease and while communicating with their distressed loved ones. Such skills are also important to work well with other members of the healthcare team. Excellent communication not only offers the best care to the patient, but also helps support team members who handle these difficult situations. The patient will also benefit from perfecting the collaboration and communication among the numerous involved physicians. Training to improve these communication skills is essential. Such training ideally starts early in the course of professional education. Several models have proven to be effective. This chapter will review the mandatory elements of a good meeting where bad news is communicated, give tools to discuss with distressed and sometimes “difficult” families, and emphasize the importance of coordinated teamwork and communication among the various physicians and other health workers involved in the patient’s care.

While the role of culture in addressing health care disparities in general and, cancer health disparities specifically is increasingly recognized, a systemic approach aimed at bolstering the cultural competence of our nation’s health care workforce is absent. Among the health outcomes, the impact of this gap is most pronounced in cancer. Ample scientific evidence exists affirming that eliminating cancer health disparities requires a multi-sectorial approach. The lack of cultural competence among frontline providers physicians, nurses, pharmacists, health educators – is only compounded by the cancer workforce crisis, a national threat to assuring quality cancer care to a growing vulnerable and increasingly culturally diverse global population. Traditional solutions to the health care workforce crisis in general and that of the cancer workforce specifically have largely failed because of a silorather than a systems approach, focusing on one specific segment of the workforce or one specific aspect of cancer care. Furthermore, much of those efforts were limited to addressing the quantitative aspect of the problem – increase the number of cancer care professionals, ignoring the equally important qualitative componentassuring a health care workforce, competent in providing cancer care across the cancer spectrum to culturally diverse populations. (C-Change 2008; Lichtveld 2009)

Quality of life, coping styles, and satisfaction with health care were assessed in 32 bone marrow transplant recipients and 22 conventional chemotherapy recipients. Subjects reported having generally good quality of life with no significant differences in quality of life or coping styles between the two groups. Quality of life was not significantly associated with age, socioeconomic status, time since diagnosis, or time since last treatment, although lower scores were associated with a passive coping style. Interestingly, bone marrow transplant recipients reported greater over-all satisfaction with health care and more contentment with the cost and convenience of health-care delivery than did conventional chemotherapy recipients.

Two bone marrow transplant recipients are described who developed nephrotic syndrome in association with hepatitis C virus (HCV) infection. Renal biopsies of both patients revealed stage I membranous glomerulonephritis. Detection of HCV genome was performed by nonisotopic in situ hybridization and reverse transcriptase polymerase chain reaction on paraffin-embedded renal biopsy specimens. Hepatitis C virus genome was detected by reverse transcription nested polymerase chain reaction on the RNA extracted from 15 5-μm paraffin sections. However, HCV genome was not revealed by nonisotopic in situ hybridization, which was likely due to the low copy number of HCV genomes present. These studies suggest that chronic HCV infection is associated with membranous glomerulonephritis.

Increasing use of bone marrow transplantation (BMT) and improved survival rates have led to growing concerns regarding the psychological adjustment of BMT recipients. However, few systematic studies have been conducted and those reported have focused primarily on the psychological functioning of BMT recipients several months or years after transplantation. In this article, the authors report normative psychological data on 51 BMT candidates assessed before hospitalization. Overall, the authors found little support for previous anecdotal reports that hypothesized increased incidences of negative affect during this preadmission period. Interestingly, however, patients' use of a passive coping style was significantly correlated with higher degrees of negative affect and psychopathology. The data reported provide a foundation for a more prospective, longitudinal assessment of BMT patients.

Cytomegalovirus (CMV) interstitial pneumonia is a frequent and often fatal complication of allogeneic bone marrow transplantation. Because therapy for CMV pneumonia was, until recently, largely ineffective, prophylactic methods were explored. This study shows that the strategy of using CMV seronegative blood products for seronegative patients with seronegative donors or weekly administration of intravenous immunoglobulin for all other patients reduced the attack rate of CMV pneumonia. The results of this study are put into the perspective of previously published data.

Five female patients, ranging in age between 22 and 36 years, presented with myelodysplastic syndromes during pregnancy between June 1982 and March 1987. Three of these five cases evolved into acute leukemia. A bone marrow transplant was attempted in the fourth. It is suggested that the association of myelodysplastic syndromes during pregnancy is more than coincidental and that acute leukemia evolves in a majority of these cases. Furthermore, refractory macrocytic anemias in pregnancy need to be carefully evaluated for a primary myelodysplastic state.

T lymphocytes play a central role in many human immunologic disorders including both autoimmune and alloimmune diseases. In hematopoietic stem cell transplant (HSCT), acute graft-versus-host-disease (GVHD) is caused by an attack on the recipient's tissues from donor allogeneic T cells. Ex vivo application of phototherapy to selectively deplete GVHD-causing cells prior to transplant may prevent GVHD. However, none of the photosensitive agents in use today have demonstrated selectivity without significant toxicity occurring in resting cells. We have designed the first-in-class, novel photosensitizer 2-Se-Cl with the ability to accumulate in pathogenic T cells in proportion to degree of oxidative phosphorylation (OXPHOS). Unique to 2-Se-Cl is the ability to potently stimulate P-glycoprotein (P-pg). Enhanced P-gp activity promotes the efficient removal of photosensitizer not sequestered in mitochondria, and protects resting lymphocytes essential for antipathogen and antitumor responses. To confirm that 2-Se-Cl selectively depletes antigen-specific immune responses, human lymphocytes were cultured with staphylococcal enterotoxin B (SEB) for 72 hours. Cells were then pulsed with 2-Se-Cl and exposed to 5 J/cm2 of light, which resulted in the impedance of OXPHOS and induction of apoptosis in stimulated T cells. After photodepletion (PD), resting cells remained intact with the ability to respond to stimulation by Toxic Shock Syndrome Toxin-1 (TSST-1) but not SEB. To evaluate the selective depletion of alloimmune responses, a well-established complete mHC antigen-mismatched murine model of HSCT was employed. To prepare the PD - treated primed splenocytes, donor C57BL/6 splenocytes were cocultured for 5 days with irradiated Balb/c splenocytes, and then photodepleted. In vitro analysis of PD - treated primed splenocytes demonstrated selective depletion of antihost immune responses by CFSE dilution, with complete retention of third-party responses (C3H/HeJ mice). On the day of HSCT, recipient Balb/c mice were irradiated with 900 cGy, and received 5x106 T cell-depleted bone marrow cells accompanied by 5x106 PD - treated (treatment group) or untreated (control group) primed splenocytes, and then monitored for signs of GVHD according to an established mouse GVHD grading system. Five animals underwent HSCT in each group in 3 independent experiments. All mice died of acute GVHD after the addition of 5x106 untreated primed C57BL/6 cells at a median of 25 days after HSCT. In contrast, > 90% of mice that received the same number of PD - treated cells survived > 60 days without evidence of GVHD (see figure). Additionally, third-party C3H/Hej mice that received the same number of PD-treated cells died of GVHD, confirming the selective depletion of the alloimmune response for BalB/c by 2-Se-Cl. The high selectivity of this novel photosensitizer may have broad applications, including targeting the bioenergetics in alloimmune, autoimmune, and malignant T cells to provide alternative treatment options and improve clinical outcomes for patients with diseases such as GVHD, systemic lupus erythematosus, or peripheral T cell lymphoma. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Purpose: 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a poly-chlorinated pyridine cholesteryl carbonate whose MOA is via bis-alkylation of DNA @ N7 - guanine and N6 - cytosine. DM-CHOC-PEN has undergone a Phase I study (allowed enrollment of subjects with advanced cancer +/- CNS involvement) and is being evaluated in a Phase II trial in subjects with advanced cancer involving the brain. Impressive objective responses and improved PFS/overall survival have been observed in subjects with NSCLC involving the CNS. The main aims of this presentation are to document a mechanism for DM-CHOC-PEN's penetration into NSCLC metastases involving the CNS via L-glutamine (GLM) transport. Methods: Human cancer cell lines [NSCLC - H2087 & H460 and SCLC - SHP-77 & H1417 - obtained from ATCC] were maintained in culture with complete RPMI (5% FBS, pen/strep/Amp. B), supplemented w/ L-glutamine [300 mg/500 mL medium, Sigma] @ 37oC and in moist 5% CO2 conditions. DM-CHOC-PEN was dissolved in tetrahydrofuran, impregnated into ChemoChads® that deliver drug 0.25 - 5 μg/mL in culture. Cells were grown in culture w/wo supplemental GLM for 36 h and then ChemoChads were added. Cytotoxicity was conducted in multi-well plates using the Cytotec® Assay and measuring IC50 values after 24 hr. All assays were conducted in triplicate. Results: All 4-cell lines grew well in complete RPMI supplemented with L-glutamine. Both SCLC cell lines grew well as clumps of small single cells in suspension, +/- GLM suppl. but were not sensitive to DM-CHOC-PEN, w/ or wo/ GLM supplements. In contrast, both NSCLC cell lines grew as coalescing islands of adhered well-differentiated cells in GLM supplemented medium, but did not grow well in GLM-free medium. Of interest, both NSCLC cell lines were sensitive to DM-CHOC-PEN (IC50 0.25-0.75 μg/mL) w/ GLM-suppl. medium, but were not sensitive (IC50 >5 μg/mL) in GLM-free medium. However, when GLM was added to the GLM-free medium w/ DM-CHOC-PEN, the cells resumed sensitivity to the drug. Similar findings have been observed for 6/7-human NSCLC explants obtained from CNS surgical samples (which will be discussed). Conclusion: The common structural similarities between DM-CHOC-PEN, GLM and Ɣ-aminobutyric acid (GABA) could allow the sharing of a transport/receptor mechanism into the cerebellum and other CNS safe havens that provide a favorable microenvironment for NSCLC cells to colonize, thrive and grow. The drug when administered IV associates with erythrocytes (∼50%), which facilitates its entry into the neoplastic cerebral circulation and now support for its transport into metastatic NSCLC involving the CNS via the GLM transport system is presented. In the absence of GLM, the GLM-transport system shuts down. Of clinical interest is that all subjects with cerebellar NSCLC lesions have responded to DM-CHOC-PEN in the clinical trials with objective responses, improved PFS (6-17+ months) and improved QOL (AACR, Abst. 1161, 2015). The cerebellum offers a unique microenvironment rich in chemical transmitters and amino acids - in particular GLM and Ɣ-aminobutyric acid (GABA). Supported by NCI/SBIR grant - R43/44CA132257. Citation Format: Lee Roy Morgan, Jr., Ed Benes, Andrew H. Rodgers, Tallat Mahmood, Roy S. Weiner, Marcus L. Ware. 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) as a cytotoxic L-glutamine agonist in non-small cell lung cancer (NSCLC) involving the CNS. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C152.

Purpose: 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN), is a poly-chlorinated pyridine cholesteryl carbonate whose MOA is via alkylation of DNA @ N7 - guanine and N6 - cytosine and via oxidative stress. DM-CHOC-PEN underwent a phase I study in patients with advanced cancer +/- CNS involvement and is being evaluated in a phase II trial in patients with primary brain cancer and brain metastases from melanoma, breast, and lung cancers. The aims are to assess clinical responses when DM-CHOC-PEN is administered I.V, at maximum tolerated dose (MTD) and to monitor safety/toxicities, pharmacokinetics, and cardiac functions - IND 68,876. Patients & Methods: In phase I, DM-CHOC-PEN was administered as a 3-hr IV infusion once every 21-days to patients with advanced cancer - melanoma (n = 3), colorectal CA (n = 4), breast (n = 3), lung (n = 8) and glioblastoma multiforme (GBM) (n = 9) - the most common tumor treated. Cohorts were treated with escalating doses from 39 to 111 mg/m2. The phase II dose schedule is 2-tiered: 85.8 mg/m2 for patients with liver involvement and 98.7 mg/m2 for patients with normal livers. Results: Forty (40) patients have been treated to date - 27 in phase I and 13 in phase II. The drug was well tolerated; the most common adverse effects were fatigue (n = 2), liver dysfunction - elevated bilirubin (Gr-3, n = 3; Gr-2, n = 1), ALT/AST (Gr-2, n = 3), alk phos (Gr-2, n = 3), nausea (Gr-1/2, n = 5) and an allergic reaction (Gr-2, n = 1). Three (3) patients with liver metastasis had hyperbilirubinemia (Gr-3 SLT) - two (2) at 98.7 mg/m2 and one (1) at 111 mg/m2 levels. No neuro/psychological, hematological, cardiac or renal toxicities were observed. PK studies revealed the following profile for DM-CHOC-PEN 98.7 mg/m2: AUC o-t = 1850 mg.h/L, CL - 3.0 L/h, T1/2 α - 3.3 h & Tβ - 79.1 h. DM-CHOC PEN and DM-PEN (metabolite) showed a rebound phenomenon at ∼50 hours post-infusion with a T release of 26.7 h for plasma and rbcs. DM-CHOC-PEN and DM-PEN were detected 3 and 15 days bound to RBCs (70 - 111 mg/m2); DM-CHOC-PEN was also detected in the urine (Cmax = 17.5 μg/mL) until day 21. The AUC was linear for all doses. DM-CHOC-PEN was detected in spinal sarcoma and in lung cancer tissues (75 & 190 ng/g, resp.) surgically obtained from patients 21-days post single injection of 39 & 98.7 mg/m2, resp. Patients receiving dexamethasone demonstrated lower blood levels of DM-CHOC-PEN along with induction of steroid esterase activities. After multiple doses, DM-CHOC-PEN also induced steroid esterase levels, which reversed within 4 weeks. Steroid esterase assays may be a valuable companion assay. Conclusion: DM-CHOC-PEN is safe at the presented dose levels and shows a favorable PK profile. To date, 15 patients have had responses with significant PFS/OS, including 10 with CNS involvement. DM-CHOC-PEN is well tolerated with manageable toxicities. Complete patient responses/toxicities will be presented. Supported by NCI/SBIR grant - R43/44CA132257 Citation Format: Roy S. Weiner, P Friedlander, T Mahmood, Adilia Hormigo, C Gordon, Y Saenger, ML Ware, VK Thirukonda, VM Patel, TJ Cosgriff, AH Rodgers, LR Morgan, G Bastian. Results from the early cancer clinical trials for 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT218. doi:10.1158/1538-7445.AM2015-CT218

This paper estimates the economic benefits of establishing a National Cancer Institute-designated center in Louisiana. Estimates of direct and indirect costs of cancer were used to derive the potential benefits of a cancer center. A fully functional cancer center should be able to prevent about 6,550 deaths over the next 10-year period implying a savings of about 23,000 disability-adjusted life years. The potential revenues to be generated through new patients from neighboring states, diversion of Louisiana patients back to the state from other out-of state facilities, and the indirect benefits derived through increased economic productivity (due to life years saved) makes the establishment of the center highly cost-effective. The benefit-cost ratio of establishing a cancer center becomes 8.5, i.e., spending one million dollars in a cancer center should generate about dollars 8.5 million worth of economic benefits for the State over a 10-year time horizon.

A total of 28 patients with chronic myelogenous leukemia (CML) in chronic phase (CP) received bone marrow allografts from HLA-matched siblings at the University of Florida between August 1984-July 1992. The present study compares the disease-free survival (DFS) for those patients who were transplanted before or after August 1988 using the same conditioning regimen. The analysis shows significant difference in 3-year DFS for those patients transplanted post- vs. pre-August 1988 (69.6% vs. 20%, respectively; P = 0.006). A decrease in pneumonitis due to different etiologies from pre-August 1988 (6/13, 46%) to post-August 1988 (1/15, 7%) was statistically significant (P = 0.029). A decrease, although statistically insignificant, in the overall incidence and severity of acute and chronic graft vs. host disease (GVHD) after August 1988 was also noticed. This study indicates significantly improved outcome for patients with CML in CP who have been treated in the University of Florida after August 1988. Better supportive care and prophylaxis for GVHD most likely contributed to such improvement.

PURPOSE: DM-CHOC-PEN is a poly-chlorinated pyridine cholesteryl carbonate whose MOA is via alkylation of DNA @ N7 – guanine and via oxidative stress. The aims of this clinical trial were to determine maximum-tolerated dose (MTD), safety, dose-limiting toxicities (DLTs), pharmacokinetics (PK) of DM-CHOC-PEN and monitor for clinical responses. METHODS: DM-CHOC-PEN was administered as a 3-hr IV infusion once every 21-days to patients with advanced cancer; melanoma (n = 3), colorectal CA (n = 3), breast (n = 3) and glioblastoma multiforme (n = 6). The trial included patients with advanced cancer +/- CNS involvement. The starting dose was 39 mg/m2 with escalations to date up to 111 mg/m2. RESULTS: Twenty-six (26) patients have been treated. The MTD was 2-tiered and defined as 85.8 mg/m2 for patients with liver involvement and 98.7 mg/m2 for patients without liver abnormalities. The most common adverse effects were fatigue (n = 2), liver dysfunction – elevated bilirubin (Gr-3, n = 3; Gr-2, n = 1), ALT/AST (Gr-2, n = 3), alk phos (Gr-2, n = 3) and an allergic reaction (Gr-2, n = 1). Three (3) patients with liver metastasis demonstrated hyperbilirubinemia (Gr-3 SLT) – 2 at the 98.7 mg/m2 and one (1) at the 111 mg/m2 levels Five (5) additional patients with liver disease have been treated at 85.8 mg/m2 level without toxicity. CONCLUSIONS: DM-CHOC-PEN is safe at the presented dose levels and has a favorable PK profile. Eight (8) patients had responses or significant PFS, including 6 with CNS involvement. A Phase II trial has begun in patients with primary brain cancer and brain metastases from melanoma, breast cancer and lung cancer.

Purpose: 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a poly-chlorinated pyridine cholesteryl carbonate whose MOA is via alkylation of DNA @ N7 - guanine and via oxidative stress. The aims of this clinical trial were to determine maximum-tolerated dose (MTD), safety, dose-limiting toxicities (DLTs), pharmacokinetics (PK) and monitor for clinical responses - IND 68,876. Patients & Methods: DM-CHOC-PEN was administered as a 3-hr IV infusion once every 21-days to patients with advanced cancer. Melanoma (n=3), colorectal CA (CRC, n=3), breast (n=3) and glioblastoma multiforme (GBM) (n=6) the most frequent diagnoses. The starting dose was 39 mg/m2 with escalations to 111 mg/m2. Results: Twenty-six (26) patients have been treated. The MTD was 2-tiered and defined as 85.8 mg/m2 for patients with liver involvement and 98.7 mg/m2 for patients without liver abnormalities. The drug was well tolerated with the most common adverse effects being fatigue (n=2), liver dysfunction - elevated bilirubin (Gr-3, n=3; Gr-2, n=1), ALT/AST (Gr-2, n=3), alk phos (Gr-2, n=3) and an allergic reaction (Gr-2, n=1). No neuro/psychological, hematological or renal toxicity have been observed. Three (3) patients with liver metastasis demonstrated hyperbilirubinemia (Gr-3 SLT) - 2 at the 98.7 mg/m2 and one (1) at the 111 mg/m2 levels Five (5) additional patients with liver disease have been treated at 85.8 mg/m2 level without toxicity. PK studies in humans revealed the following profile for DM-CHOC-PEN 70 mg/kg: AUC o-t = 980 mg.h/L, CL - 0.141L/h, T1/2 α - 0.63 h & Tβ - 24.1 h. DM-CHOC PEN and DM-PEN (metabolite) showed a rebound phenomenon @ ∼ 50 hours post-infusion with a T release of 26.7 h. Same phenomenon is observed in RBCs (estimation using Monolix 3.2). DM-CHOC-PEN and DM-PEN were detected 3 and 15 days bound to RBCs (after 70 mg/m2); DM-CHOC-PEN was also detected in the urine (Cmax=17.5 µg/mL) until day 21. The AUC was linear for all doses. Similar to the rats, the total lipid profiles in the patients were erratic (2o to the lipid emulsion vehicle) during the 3-h infusion period, and then returned to pre-treatment values after 24 h. The triglycerides were the most significantly affected. DM-CHOC-PEN could be identified in spinal sarcoma tissue (in 190 ng/g quantities) obtained surgically from a patient 21- days post single injection of 39 mg/m2. Patients receiving dexamethasone demonstrated lower blood levels of DM-CHOC-PEN, 2o induction of steroid esterase activities. The latter will be discussed. Conclusion: DM-CHOC-PEN is safe at the presented dose levels and shows a favorable PK profile. Eight (8) patients have had responses or significant PFS, including 6 with CNS involvement. Patient responses/toxicities will be presented. A Phase II trial has begun in patients with primary brain cancer and brain metastases from melanoma, breast cancer and lung cancer. Supported by NCI/SBIR grant - R43/44CA132257. Citation Format: Roy S. Weiner, Philip Friedlander, Craig Gordon, Yvonne Saenger, Tallat Mohmood, Marcus Ware, AH Rogers, Gerard Bastian, S Urien, LR Morgan. A phase I cancer clinical trial for 4-demethyl-4cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) IND 68.876. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT225. doi:10.1158/1538-7445.AM2014-CT225

PURPOSE: Medical care for clinical trials is often not reimbursed by insurers, primarily because of concern that medical care as part of clinical trials is expensive and not part of standard medical practice. In June 2000, President Clinton ordered Medicare to reimburse for medical care expenses incurred as part of cancer clinical trials, although many private insurers are concerned about the expense of this effort. To inform this policy debate, the costs and charges of care for patients on clinical trials are being evaluated. In this Association of American Cancer Institutes (AACI) Clinical Trials Costs and Charges pilot study, we describe the results and operational considerations of one of the first completed multisite economic analyses of clinical trials. METHODS: Our pilot effort included assessment of total direct medical charges for 6 months of care for 35 case patients who received care on phase II clinical trials and for 35 matched controls (based on age, sex, disease, stage, and treatment period) at five AACI member cancer centers. Charge data were obtained for hospital and ancillary services from automated claims files at individual study institutions. The analyses were based on the perspective of a third-party payer. RESULTS: The mean age of the phase II clinical trial patients was 58.3 years versus 57.3 years for control patients. The study population included persons with cancer of the breast (n = 24), lung (n = 18), colon (n = 16), prostate (n = 4), and lymphoma (n = 8). The ratio of male-to-female patients was 3:4, with greater than 75% of patients having stage III to IV disease. Total mean charges for treatment from the time of study enrollment through 6 months were similar: $57,542 for clinical trial patients and $63,721 for control patients (1998 US$; P = .4) CONCLUSION: Multisite economic analyses of oncology clinical trials are in progress. Strategies that are not likely to overburden data managers and clinicians are possible to devise. However, these studies require careful planning and coordination among cancer center directors, finance department personnel, economists, and health services researchers.

We treated 20 women with locally advanced breast cancer between January 1991 and September 1996. The treatment regimen included 4 cycles of intensive doxorubicin (30 mg/m2/d on 3 consecutive days every 2 weeks with G-CSF support), followed by appropriate surgery, followed by high dose therapy with cyclophosphamide, carboplatin and thiotepa (STAMP V, CTCb). Of the 20 patients, seven presented with inflammatory breast cancer, three with Stage IIIB, seven with stage IIIA, one with multifocal Stage IIB and two with Stage IV M1 (ipsilateral supraclavicular lymph node involvement) (including one who had an inflammatory primary) disease. Six patients had not undergone mastectomy at the time of entering the protocol. These six received the doxorubicin in a neoadjuvant fashion and were thus evaluable for tumor response. The remaining 14 received doxorubicin as adjuvant therapy prior to intensification and transplantation. All patients underwent local-regional radiation therapy and were placed on oral tamoxifen. Doxorubicin was well tolerated in this schedule with all but three patients receiving all their cycles on schedule. Both BM and PBPC were easily collected after this regimen and, when reinfused, resulted in the prompt recovery of granulocytes (median 11 days to 500 absolute granulocyte count) and platelets (median 13 days to 20,000 platelets). The six patients who received doxorubicin prior to mastectomy all had major clinical responses, but were found to have microscopic focii of breast cancer in the mastectomy specimens. The overall treatment was well tolerated with the exception of one treatment-related death (5%). The overall and relapse free survival are 70% and 58% respectively with a median follow-up of 40 months (range 12-74 months). When the Stage IV patients are censored, the relapse-free survival rate is 69%. In the bone marrow transplant phase of treatment, the major non-hematologic toxicities were stomatitis (70%) and anorexia requiring parental nutrition (75%).

Introduction: DM-CHOC-PEN is a polychlorinated pyridine cholesteryl carbonate, which has completed a Phase I clinical trial in patients with advanced cancer - IND 68,876 (AACR 1185, 2013). DM-CHOC-PEN produced responses with improved cerebral progression free intervals (CPFI) in patients with CNS melanoma, breast, and lung cancers. CNS melanoma is of especial interest since there is no acceptable therapy for this stage of disease. DM-CHOC-PEN's principle MOA is via alkylation of DNA with N7-guanine, however, in melanoma, there is also generation of reactive oxygen species (ROS) via the DOPA/melanin pathway resulting in melanin encapsulation of melanoma cells and cell death. In mice the drug accumulated in intracerebrally/cerebellar implanted tumors, and not in normal CNS tissue, with no Purkinje cell degeneration; in contrast to drugs such as penclomedine, phencyclidine, ibogaine, etc. that also accumulate in the cerebellum but with cellular destruction. Patients with metastatic CNS cancer treated with DM-CHOC-PEN demonstrated some euphoria, but no CNS toxicity. Methods: B-16 melanoma cells were cultured in RPMI media with 5% FBS and pen/strep at 37oC in a CO2 incubator. Drugs were added to the cells during growth phase and removed after 16 hrs; responses were monitored. Adult female C57BL mice in groups of 5-6 with growing B-16 melanoma were dosed IP daily (75-200 mg/kg) for 5 days with DM-CHOC-PEN or saline and monitored daily until death or moribund and sacrificed. Animals were sacrificed, brain tumor and normal tissue removed and prepared for histology exams. Patients in the Phase I trial (DTI-021) with CNS melanoma were treated with 86.5 mg/m2 IV q 21 days and CNS lesions were monitored with MRI during the Phase I clinical trial (DTI-021) [AACR 1185, 2013]. Results: In vitro, DM-CHOC-PEN had an IC50 0.5 µg/mL against B-16 melanoma cells. Mice bearing B-16 melanoma treated with DM-CHOC-PEN (200 mg/kg/d x 5d, IP) alone vs. saline controls demonstrated %ILS of 142% - supporting the in vitro observations. Patients with CNS melanoma treated with DM-CHOC-PEN demonstrated objective responses and improved CPFI with associated melanin deposits similar to those seen with mice. DM-CHOC-PEN induced ROS via DOPA/DOPA oxidase-melanin deposits and cell death in mice with melanoma. Discussions - DM-CHOC-PEN bound to erythrocytes crosses the BBB and accumulates in CNS melanoma (not normal tissue) with intracellular DOPA-DOPA quinone and melanin formation that interrupts cancer cell metabolism and cellular death via ROS. The drug is not recycled into the systemic circulation. Electronic modeling studies support DM-CHOC-PEN's ability to act as a pyridinium co-factor in the transfer of electrons from DOPA to cytochrome c and the intermediary metabolism pool with generation of ROS. Oxidative stress and ROS generation from a DM-CHOC-PEN/DOPA-melanin pathway has now been confirmed. Cerebellar lesions appear to be especially sensitive. Conclusion: Responses and CPFI for patients with CNS cancers (and no CNS toxicity) seen in the Phase I study have been reported [AACR 1185, 2013]. The principle human toxicity was hepatic. The role for the DOPA/DOPA quinone-melanin pathway with ROS formation will be presented as a key MOA for the drug, with emphasis on cerebellar melanoma lesions. Supported in part by: NCI/ SBIR grants R43/44CA85021 and R43/44CA132257. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A264. Citation Format: Lee Roy Morgan, Edmund Benes, Andrew H. Rodgers, Roy S. Weiner, Marcus L. Ware, Philip Friedlander, Yvonne Saenger, Craig Gordon, Tallat Mahmood, Branko Jursic, Gerard Bastian. Response of CNS melanoma to 4-demethyl-4-cholestrylcarbonylpenclomedine (DM-CHOC-PEN) and cell death. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A264.

Purpose: 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a poly-chlorinated pyridine cholesteryl carbonate whose MOA is via alkylation of DNA @ N7 - guanine and induces oxidative stress. The main aims of this first-in human trial were to determine maximum-tolerated dose (MTD), safety, dose-limiting toxicities (DLTs) and pharmacokinetics (PK) of DM-CHOC-PEN - IND 68,876. Patients & Methods: DM-CHOC-PEN was administered as a 3-hr IV infusion once every 21-days in 21 patients with melanoma (n=3), colorectal CA (CRC, n=3), and glioblastoma multiforme (GBM) (n= 6); the most frequent diagnoses. The trial allowed enrollment of patients with advanced cancer +/- CNS involvement. The starting dose was 39 mg/m2 with escalations to date up to 98.7 mg/m2. Results: Twenty-one (21) patients have been treated to date. MTD was 2-tiered and defined as 85.8 mg/m2 for patients with liver involvement and, for patients without liver abnormality it is not yet defined but is at least 98.7 mg/m2, for the latter population. The drug was well tolerated with the most common adverse effects being fatigue (n=2), liver dysfunction - elevated bilirubin (Gr-3, n=2; Gr-2, n=1), ALT/AST (Gr-2, n=3), alk phos (Gr-2, n=3) and an allergic reaction (Gr-2, n=1). No neuro/psychological, hematological or renal toxicity observed. Two (2) patients with liver metastasis demonstrated hyperbilirubinemia (Gr-3 SLT) at the 98.7 mg/m2 dose level. Five (5) additional patients with liver disease have been treated at 85.8 mg/m2 level without toxicity - the MTD for that stage of cancer. Dose cohorts @ 98.7 mg/m2 are in progress for non-liver staged patients. PK studies in humans revealed the following profile for DM-CHOC-PEN 70 mg/kg: AUC o-t = 980 mg.h/L, CL - 0.141L/h, T1/2 α - 0.63 h & Tβ - 24.1 h. DM-CHOC PEN and DM-PEN showed a rebound phenomenon @ ∼ 50 hours post-infusion with a T release of 26.7h. Same phenomenon is observed in RBCs (estimation using Monolix 3.2). DM-CHOC-PEN and DM-PEN were detected 3 and 15 days bound to RBCs (after 70 mg/m2); DM-CHOC-PEN was also detected in the urine (Cmax=17.5 μg/mL) until day 15. The AUC was linear for all doses. Similar to the rats, the total lipid profiles in the patients were erratic (2o to the lipid emulsion vehicle) during the 3-h infusion period, and then returned to pre-treatment values after 24 h. The triglycerides were the most significantly affected. DM-CHOC-PEN could be identified in spinal sarcoma tissue (in 190 ng/g quantities) obtained surgically from a patient 21- days post single injection of 39 mg/m2. Conclusion: DM-CHOC-PEN is safe at the presented dose levels and shows a favorable PK profile. Seven (7) patients have observed responses or significant PFS, including 5 with CNS involvement. DM-CHOC-PEN is well tolerated with manageable toxicities. Complete patient responses/toxicities will be presented. Supported by NCI/SBIR grant -1R43CA132257. Citation Format: Roy S. Weiner, Philip Friedlander, Craig Gordon, Yvonne Saenger, Marcus Ware, Tallat Mahmood, AH Rodgers, Gerard Bastian, S Urien, Lee Roy Morgan. A first-in-humans phase I cancer clinical trial for 4-Demthyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1185. doi:10.1158/1538-7445.AM2013-1185

4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a polychlorinated pyridine cholesteryl carbonate, which is active vs. intracranially (IC) implanted human xenograft models - U251 and D54 glioblastoma and MX-1 breast cancer (%LTS/CR): +29/25 and +20/17, resp. and has a MOA via alkylation of DNA @ N7 - guanine (CCP, 64, 829, 2009). DM-CHOC-PEN's preclinical rodent single IV dose toxicity studies documented the following landmark values: for mice - LD10/50 136/385 mg/kg; & for rats - LD10 100 mg/kg. DM-CHOC-PEN is metabolized to 4-demethyl-PEN (DM-PEN) and cholesterol. The DLT in rats was hypercholesteremia - 2nd to release of cholesterol from the oxycarbonate moiety. The LDL-cholesterol was increased 30 fold at doses of 200 and 300 mg/kg, which returned to normal values - predominantly as the HDL-cholesterol by Day 15. Plasma and erythrocyte DM-CHOC-PEN and metabolites DM-PEN/cholesterol were assayed vs. time by HPLC. Overall, PK values in rats revealed the following profile for DM-CHOC-PEN @ 100 mg/kg: AUC o-t = 1.05 mg (h/L), T1/2β = 0.51 (h), T1/2β = 2.48 (h) & CL = 3.04 (L/h) [a two compartment model]. The AUC was linear for 100, 200, 300 mg/kg doses. There were no differences between males and females. For the Phase I clinical trial (IND 68,876), the calculated (from mice) initial single dose for DM-CHOC-PEN was 39 mg/m2 administrated IV q 21-days with 40% dose escalations q 3-cycles until SLTs were identified. To date, doses of 39, 55, 70 mg/m2 have been administered to patients without toxicity. DM-CHOC-PEN PK modeling revealed a central compartment (cpt) which released the drug into a peripheral compartment (pct) with CL - 0.141L/h, T1/2 α - 0.63 h & Tα - 24.1 h. DM-CHOC-PEN & DM-PEN showed an important rebound phenomenon @ ∼ 50 hours post-infusion with Trelease 26.7h (for both).Same phenomenon is observed in rbcs (estimation using Monolix 3.2). DM-CHOC-PEN and DM-PEN were detected for 3 and 15 days, resp., bound to rbcs (after 70 mg/m2); DM-CHOC-PEN was also detected in the urine (Cmax=17.5 µg/mL) until day 15. Similar to rats, the total lipid profiles (cholesterol and triglycerides) for the patients were erratic during the 3-h IV infusion period (2o to the lipid emulsion vehicle) and then returned to pre-treatment values after 24 h; triglycerides most significantly affected. In 1-patient, DM-CHOC-PEN could be identified in sarcoma tissue metastatic to the spine in 190 ng/g quantities, which was obtained 21-days post IV infusion with 39 mg/m2. Five (5) patients have been treated to date; no hematological, neurotoxic or psychological alterations have been identified. Thus, DM-CHOC-PEN is well tolerated with manageable toxicities to date; the trial continues. An update on patient responses/toxicities will be presented. Comparative PK profiles of DM-CHOC PEN and metabolite in plasma, RBC and urine are analyzed and will be presented here. Supported by NCI/SBIR grant - 1R43CA132257. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 758. doi:1538-7445.AM2012-758

Angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) can best be described as a disorder of T-cells resulting in amplification of the B-cell response and clinical symptoms of lymphadenopathy, fever, hepatosplenomegaly, and a variety of blood abnormalities. Pure red cell aplasia (PRCA), an autoimmune disorder resulting in selective aplasia of the erythroid series, has only rarely been associated with AILD. Herein we report three cases of AILD and PRCA. Serum from one patient was available for study and contained a dose-dependent inhibitor of the CFU-E but not CFU-GM cultures from normal bone marrow. This activity was found in the globulin fraction after ammonium sulfate precipitation. Patients with AILD are known to make antibodies to many autologous epitopes, and the most well-characterized mechanism of PRCA involves antibodies to red cell precursors. Our serum data are consistent with the hypothesis that such an antibody existed in our patient. Aggressive treatment of these patients resulted in transient improvement in two; however, all three died without achieving a durable complete remission with two dying of infectious complications.

To define the basic state-of-the-art medical care of the patients after bone marrow transplantation as practiced by the Eastern Cooperative Oncology Group.Studies examining the role of bone marrow transplantation in the care of neoplastic disorders identified using computer and bibliographic searches.More than 500 articles, book chapters, and abstracts from meetings, covering all therapeutic and diagnostic aspects of the patient having bone marrow transplantation were critically reviewed; information from over 200 publications is included.Enormous progress has been made in understanding the biology, therapy, and prophylaxis strategies of bone marrow transplantation and in extending the range of potential marrow donors to include unrelated persons. Dramatic advances have occurred in the prevention of serious infection, including cytomegalovirus infection, formerly a cause of a high rate of mortality. The advent of newer-combination, high-dose chemotherapy regimens and advances in cryopreservation and in vitro marrow purging techniques have led to increased use and greater efficacy of autologous transplantation. Recent advances using recombinant hematopoietic growth factors and autologous peripheral stem cells are likely to reduce morbidity and mortality and significantly shorten the length of hospitalization and the cost of bone marrow transplantation.Bone marrow transplantation now is a common procedure done throughout the world. Cooperative groups have assumed a major role in conducting clinical trials. A standardized approach defining basic standards of care will assure uniformity of management, better interpretation of data, and continued progress in the care of the patient who has had a bone marrow transplantation. Basic research and clinical trials are ongoing to define better methods for the treatment and prevention of graft-versus-host disease and hepatic veno-occlusive disease.

Introduction: 4-Demethyl-4-cholesteryloxycarbonyl-penclomedine (DM-CHOC-PEN) is a polychlorinated pyridine cholesteryl carbonate, which is in Phase I clinical trials in patients with advanced cancer - IND 68,876. DM-CHOC-PEN is active vs. intracranially (IC) implanted human xenograft models - U251 and D54 glioblastoma and MX-1 breast cancer and recently found to be active vs. B-16 melanoma - 142% ILS. DM-CHOC-PEN's MOA is via alkylation of DNA @ N7 - guanine, as well as converting melanoma cells into a melanotic Go phase with cell death. Not all cells were converted into Go phase and senescence, thus the interest in designing a binary drug approach for DM-CHOC-PEN, as an improvement in treatment for melanoma. A number of agents are cytotoxic vs. B-16 cells in vitro and in vivo; however, 4-hydroperoxyifosfamide (HOOI), which is converted to isophosphoramide mustard (IPM) in vivo, demonstrated the best %ILS. The latter drug has been chosen as a companion with DM-CHOC-PEN in the present binary drug study vs. B-16 mouse melanoma. Methods: B-16 melanoma cells were cultured using RPMI media with 10% FBS and pen/strep @ 37° C in a CO2 incubator. Drugs were added to the cells in a growth phase and removed after 8–12 h. Adult female C57BL mice in groups of 5–6 mice were implanted subcutaneously (SC) with B-16 mouse melanoma (106 cells) and when SC nodules were palpable the mice were dosed IP daily (200 mg/kg) for 5-days with DM-CHOC-PEN followed by HOOI administered IP @ varying doses and daily/weekly schedules and monitored daily until death. Mice with SC B-16 melanoma were dosed with single agents - DM-CHOC-PEN, HOOI, cis-platinum and temozolamide, which were used as controls. Tumor tissue was extracted with dichloromethane, and assayed per HPLC and NMR. Results: In vitro, DM-CHOC-PEN and HOOI, as single agents, had IC50 of 0.5 and 0.8 μg/mL vs. B-16 melanoma cells, resp. Mice bearing SC B-16 melanoma treated with DM-CHOC-PEN (200 mg/kg/d × 5d, IP) alone vs. saline controls demonstrated %ILS of 142%; thus supporting the in vitro observations. In vivo in the B-16 melanoma model, cis-platinum as a single agent had a %ILS = 0%, but for HOOI it was 85%. In 2-drug studies, DM-CHOC-PEN plus cis-platinum together (in theoretical therapeutic ranges) were too toxic in combination, however, the %ILS for DM-CHOC-PEN plus HOOI was 173%. Tumor tissue was removed within 2-days of treating mice with DM-CHOC-PEN, extracted and revealed 75 μg/g tumor tissue of DM-PEN, a metabolite. Discussion: HOOI is a S-phase alkylating agent that is an appropriate 2nd agent to kill cells escaping from the DM-CHOC-PEN - induced Go phase induction. To date, the best treatment regimen was DM-CHOC-PEN (200 mg/kg/d × 5d) followed by HOOI (90 mg/d × 3d) - %ILS = 173. The finding that melanoma tissue extracts resulted in μg of DM-PEN (the metabolite) is in agreement with the pharmacokinetic findings observed for DM-CHOC-PEN in rats and humans, which will be reviewed. The binary drug combination will be reviewed with the FDA. Supported in part by: NCI SBIR grants - R43/44CA85021. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B219.

PURPOSE The Eastern Cooperative Oncology Group conducted a prospective study of postremission high-dose chemotherapy and autologous bone marrow transplantation (autoBMT) in a group of uniformly treated adults with de novo acute myeloid leukemia (AML) to evaluate whether intensive, myeloablative therapy in first complete remission (CR) could improve the disease-free survival. PATIENTS AND METHODS After initial CR was induced by the combination of daunorubicin, cytarabine, and thioguanine, patients not eligible for allogeneic bone marrow transplantation (alloBMT) were offered autoBMT. Within a median of 2 months after CR, and without intervening postremission therapy, bone marrow was obtained, purged by exposure to 4-hydroperoxycyclophosphamide (4-HC), and cryopreserved. High-dose therapy consisted of oral busulfan over 4 days (16 mg/kg total) followed by intravenous (IV) cyclophosphamide 50 mg/kg daily for 4 days. The cryopreserved marrow was then reinfused. RESULTS Of the 39 patients scheduled for autoBMT, four relapsed before transplantation. Two of the 35 (6%) transplant patients died of transplant-related complications, and 11 (33%) relapsed a median of 8 months after marrow reinfusion. No relapse has occurred after 24 months posttransplant. With a median follow-up of 31 months, the median disease-free survival period for all 39 patients has not been reached; however, 54% +/- 16% of patients are projected to be alive and disease-free at 3 years. CONCLUSION Long-term, disease-free survival after autoBMT in AML seems to be better than the outcome after conventional-dose postremission therapy and rivals the results of alloBMT.