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Additional results for dual probe EGFR and ERBB2 FISH from Patients 9, 30 and 32.

CONSORT diagram

Supplementary Figure Legends

Supplemental Figure S4. Progression-free survival Kaplan-Meier curves based on PET and ctDNA parameters. A. PFS based on baseline SUV categorized into lower and higher than median. B. PFS based on baseline tumor glycolysis level lower or higher than median. C. PFS based on baseline metabolic tumor volume (MTV) lower or higher than median.

Supplementary Data from Safety and Feasibility of PARP1/2 Imaging with 18F-PARPi in Patients with Head and Neck Cancer

Supplemental Figure S3. A. Waterfall plot based on RECIL criteria. RECIL introduces the minimal response category which is a 10-30% reduction in the sum of longest diameters of target lesions. B. Event-free survival Kaplan-Meier curve.

Supplemental Figure S2. A. Comparison of treatment-related and -unrelated adverse events occurring in >10% of evaluable patients.

Purpose:We performed a first-in-human clinical trial. The aim of this study was to determine safety and feasibility of PET imaging with 18F-PARPi in patients with head and neck cancer.Patients and Methods:Eleven patients with newly diagnosed or recurrent oral and oropharyngeal cancer were injected with 18F-PARPi (331 ± 42 MBq), and dynamic PET/CT imaging was performed between 0 and 25 minutes postinjection. Static PET/CT scans were obtained at 30, 60, and 120 minutes postinjection. Blood samples for tracer concentration and metabolite analysis were collected. Blood pressure, ECG, oxygen levels, clinical chemistry, and complete blood count were obtained before and after tracer administration.Results:18F-PARPi was well-tolerated by all patients without any safety concerns. Of the 11 patients included in the analysis, 18F-PARPi had focal uptake in all primary lesions (n = 10, SUVmax = 2.8 ± 1.2) and all 18F-FDG–positive lymph nodes (n = 34). 18F-PARPi uptake was seen in 18F-FDG–negative lymph nodes of 3 patients (n = 6). Focal uptake of tracer in primary and metastatic lesions was corroborated by CT alone or in combination with 18F-FDG. The overall effective dose with 18F-PARPi PET was 3.9 mSv – 5.2 mSv, contrast was high [SUVmax(lesion)/SUVmax(trapezius muscle) = 4.5] and less variable than 18F-FDG when compared with the genioglossus muscle (1.3 vs. 6.0, P = 0.001).Conclusions:Imaging of head and neck cancer with 18F-PARPi is feasible and safe. 18F-PARPi detects primary and metastatic lesions, and retention in tumors is longer than in healthy tissues.

Supplemental Figure S1. Dosing of patients on study. A. MCL cohort. B. FL cohort. C. DLBCL cohort.

Purpose: Activation of Bruton tyrosine kinase (BTK) and phosphatidylinositol-3-kinase (PI3K) represent parallel, synergistic pathways in lymphoma pathogenesis. As predominant PI3Kδ inhibition is a possible mechanism of tumor escape, we proposed a clinical trial of dual BTK and pan-PI3K inhibition. Patients and Methods: We conducted a single-center phase I/Ib trial combining a BTK inhibitor (ibrutinib) and a pan-PI3K inhibitor (buparlisib) in 37 patients with relapsed/refractory (R/R) B-cell lymphoma. Buparlisib and ibrutinib were administered orally, once daily in 28-day cycles until progression or unacceptable toxicity. The clinical trial is registered with clinicaltrials.gov, NCT02756247. Results: Patients with mantle cell lymphoma (MCL) receiving the combination had a 94% overall response rate (ORR) and 33-month median progression-free survival; ORR of 31% and 20% were observed in patients with diffuse large B-cell lymphoma and follicular lymphoma, respectively. The maximum tolerated dose was ibrutinib 560 mg plus buparlisib 100 mg and the recommended phase II dose was ibrutinib 560 mg plus buparlisib 80 mg. The most common grade 3 adverse events were rash/pruritis/dermatitis (19%), diarrhea (11%), hyperglycemia (11%), and hypertension (11%). All grade mood disturbances ranging from anxiety, depression, to agitation were observed in 22% of patients. Results from serial monitoring of cell-free DNA samples corresponded to radiographic resolution of disease and tracked the emergence of mutations known to promote BTK inhibitor resistance. Conclusions: BTK and pan-PI3K inhibition in mantle cell lymphoma demonstrates a promising efficacy signal. Addition of BCL2 inhibitors to a BTK and pan-PI3K combination remain suitable for further development in mantle cell lymphoma.

Purpose: 124I-PU-H71 is an investigational first-in-class radiologic agent specific for imaging tumor epichaperome formations. The intracellular epichaperome forms under cellular stress and is a clinically validated oncotherapeutic target. We conducted a first-in-human study of microdose 124I-PU-H71 for PET to study in vivo biodistribution, pharmacokinetics, metabolism, and safety; and the feasibility of epichaperome-targeted tumor imaging. Experimental Design: Adult patients with cancer (n = 30) received 124I-PU-H71 tracer (201±12 MBq, Results: 124I-PU-H71 PET detected tumors of different cancer types (breast, lymphoma, neuroblastoma, genitourinary, gynecologic, sarcoma, and pancreas). 124I-PU-H71 was retained by tumors for several days while it cleared rapidly from bones, healthy soft tissues, and blood. Radiation dosimetry is favorable and patients suffered no adverse effects. Conclusions: Our first-in-human results demonstrate the safety and feasibility of noninvasive in vivo detection of tumor epichaperomes using 124I-PU-H71 PET, supporting clinical development of PU-H71 and other epichaperome-targeted therapeutics.

Purpose: We performed a first-in-human clinical trial. The aim of this study was to determine safety and feasibility of PET imaging with 18F-PARPi in patients with head and neck cancer. Patients and Methods: Eleven patients with newly diagnosed or recurrent oral and oropharyngeal cancer were injected with 18F-PARPi (331 ± 42 MBq), and dynamic PET/CT imaging was performed between 0 and 25 minutes postinjection. Static PET/CT scans were obtained at 30, 60, and 120 minutes postinjection. Blood samples for tracer concentration and metabolite analysis were collected. Blood pressure, ECG, oxygen levels, clinical chemistry, and complete blood count were obtained before and after tracer administration. Results: 18F-PARPi was well-tolerated by all patients without any safety concerns. Of the 11 patients included in the analysis, 18F-PARPi had focal uptake in all primary lesions (n = 10, SUVmax = 2.8 ± 1.2) and all 18F-FDG–positive lymph nodes (n = 34). 18F-PARPi uptake was seen in 18F-FDG–negative lymph nodes of 3 patients (n = 6). Focal uptake of tracer in primary and metastatic lesions was corroborated by CT alone or in combination with 18F-FDG. The overall effective dose with 18F-PARPi PET was 3.9 mSv – 5.2 mSv, contrast was high [SUVmax(lesion)/SUVmax(trapezius muscle) = 4.5] and less variable than 18F-FDG when compared with the genioglossus muscle (1.3 vs. 6.0, P = 0.001). Conclusions: Imaging of head and neck cancer with 18F-PARPi is feasible and safe. 18F-PARPi detects primary and metastatic lesions, and retention in tumors is longer than in healthy tissues.

Background: WBRT is a standard therapy for metastatic breast cancer (MBC) patients (pts) with brain metastases (BM), but disease progression in the brain is common. Sorafenib, a tyrosine kinase inhibitor with anti-VEGF activity, has demonstrated anti-tumor efficacy in MBC and radiosensitizing activity preclinically. [18F] 3'deoxy-3'-fluorothymidine (FLT) is a new PET tracer which correlates with cellular proliferation and may improve response assessment in the brain. Methods: A phase I trial of sorafenib with WBRT in MBC pts with BM was conducted using a 3+3 design. Sorafenib was given orally daily at the start of WBRT for a total of 21 days with 3 doses levels: 200mg, 400mg, and 600mg. The primary endpoints were to determine a maximum tolerated dose (MTD) and to evaluate safety and toxicity. The secondary endpoint was central nervous system progression-free survival (CNS-PFS). Macdonald Criteria were used for response assessment with serial MRI brain imaging. Key eligibility criteria include MBC with new or progressive ≥ 1cm BM, ECOG PS 0-2, non-escalating corticosteroid dose, and no other concurrent anti-tumor therapy except trastuzumab. In parallel, we conducted a correlative FLT-PET imaging study (baseline, 7-10 days (FU1), and 10-12 weeks (FU2) after the WBRT) to assess radiographic changes among pts receiving WBRT + sorafenib and in a separate WBRT only cohort. FLT standard uptake value (SUV) and kinetic parameter data were obtained. Results: 13 pts were treated in the dose escalation phase and evaluable for dose-limiting toxicity (DLT). The median age was 56 years (range: 43-77). There were 4 HER2 positive (31%) and 3 triple negative (23%) pts. 2 pts had prior stereotactic radiosurgery. DLTs were: Grade (G) 4 increased lipase at 200mg (1 pt) and G3 rash at 400mg (3 pts) level. MTD was determined to be 200mg. 10 pts were evaluable for response (at least 1 follow up brain imaging). The overall response rate was 70%: 4 complete responses (CR) + 3 partial responses. All 13 pts were evaluated for CNS PFS with a median follow up of 29.7 months (min 19.6, max 57.4mo). Median CNS-PFS was 8.2 months (95%CI: 3.4-31.8). Median OS was 15.4 months (95% CI: 3.4-NR). A total of 10 pts with WBRT and sorafenib and 5 pts with WBRT only were enrolled in the FLT-PET study: all 15 pts had baseline FLT PET, 14 with FU1, and 9 with FU2. 55 baseline lesions, 38 at FU1 and 15 at FU2 were observed and analyzed. All lesions with FLT uptake had MRI correlates. Decline in average SUVmax of ≥25% was seen in 9/10 (90%) of WBRT+sorafenib and 2/4(50%) of WBRT only pts at FU1. A complete disappearance of FLT uptake was noted in 1 pt at FU1 and 2 more pts at FU2. Conclusions: Concurrent WBRT with sorafenib appears safe at 200mg daily dose with a higher rate of CR compared to historical WBRT data. We are currently enrolling patients in the safety-expansion cohort. This combination should be considered for further efficacy evaluation. Additional analysis of FLT-PET as a complementary imaging modality to MRI is currently ongoing. Clinical trial registry: NCT01724606 and NCT01621906. Support: Bayer, Susan G Komen, ASCO Gianni Bonadonna Breast Cancer Award Citation Format: Morikawa A, Jhaveri K, Grkovski M, Tang K, Humm JL, Holodny A, Beal K, Schoder H, Seidman AD. A phase I trial of sorafenib with whole brain radiotherapy (WBRT) in breast cancer patients with brain metastases and a correlative study of FLT-PET brain imaging in patients receiving WBRT with or without sorafenib [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-19-03.

Prostate cancer (PC) is the second most common cause of cancer-related deaths in males in the United States (U.S.). In the United States, an estimated 191,930 new cases will be diagnosed in 2020, resulting in 33,330 deaths, representing 10.4% of all cancer-related deaths in men in the U.S. Over the past decade, preclinical studies have demonstrated that androgen receptor (AR) signaling is a principal driver of prostate cancer, and androgen deprivation therapy (ADT) has been a mainstay in the treatment of PC. Although most PCs are initially sensitive to ADT, the duration of response is variable, and relapse invariably occurs in the transition to metastatic castration-resistant prostate cancer (mCRPC) the most lethal form of the disease. A significant proportion of mCRPCs exhibit alteration (amplification and mutation) of the AR gene. Notably, localized castration sensitive prostate cancer (CSPC) rarely demonstrates alterations of AR. This observation indicates that the alteration of AR likely results from exposure to systemic therapies rather than acting as a driver from primary CSPC to more aggressive disease. For mCRPC patients, many initially respond to second-line AR inhibitors (eg. enzalutamide and abiraterone) or docetaxel-based chemotherapy, however durable responses are rare. Therefore, it is vital to investigate additional therapeutic strategies to delay or prevent the transition of CSPC to mCRPC. Earlier studies showed that the survival of malignant cells after anti-cancer therapies could be due to increase expression in anti-apoptotic proteins, such as the Bcl-2 family of proteins. In our current study, we observed that treatment with androgen inhibits but AR inhibitors (eg enzalutamide, apalutamide) restore Bcl2 expression in human CSPC cell lines indicating possible direct negative-regulation of the Bcl2 by the AR-signaling pathway. Experimentally we also showed that overexpression of BCL2 in human CSPC cells acts as an early mediator of ADT resistance in CSPC. Cell growth assays showed an overall strong additive effect on growth inhibition with enzalutamide in-combination with the Bcl-2 inhibitor (venetoclax) on human CSPC cells. Our in-vivo isograft tumor growth results were consistent with the in-vitro data where we observed a significant decrease in tumor volume and an increase of overall survival when mice treated with enzalutamide and venetoclax in combination as compared to either of the drugs when treated alone. Our current study for the first time develops a rationale for combining ADT with Bcl2 targeted therapies for CSPC. We believe this combination will show great potential for future clinical trials of high-risk CSPC patients and may block or delay the ADT-induced shift from CSPC to mCRPC. Citation Format: Rahim Hirani, Subhiksha Nandakumar, Teja Kalidindi, Deborah Fidele, Harisha Rajanala, Ying Mazzu, Yuki Yoshikawa, Lina Jehane, Gwo-Shu Mary Lee, Elisa de Stanchina, Adam Sowalsky, Michael J. Morris, Heiko Schoder, Naga Vara Kishore Pillarsetty, Lorelei A. Mucci, Daniel Danila, Goutam Chakraborty, Philip W. Kantoff. Bcl-2 inhibitor enhances anti-androgen therapy induced regression of castration sensitive prostate cancer [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 979.

Background: We recently demonstrated that biallelic as well as monoallelic loss of the DNA damage response (DDR) gene BRCA2 in prostate cancer (PC) cell lines and mCRPC organoids leads to an aggressive form of PC and early androgen deprivation therapy (ADT) resistance (Chakraborty et al.). Clinical studies have established that DDR deficiency is generally associated with a poor prognosis. Very recently, immunohistochemical analysis of mCRPC patient samples by Paschalis et al. revealed that defects in DDR genes (in particular BRCA2 and ATM) are associated with increased prostate-specific membrane antigen (PSMA; folate hydrolase, FOLH1) expression on the cell membrane. PSMA expression can be measured non-invasively in pre-clinical models and human subjects using one of the several positron emission tomography (PET) imaging agents such as [68Ga]-PSMA11 or [124I]-MSK-PSMA11 that are being evaluated in pre-clinical and/or clinical setting. Therefore, we hypothesized that upregulation of PSMA expression can be a marker for BRCA2 loss and this increased expression can be quantified using PET agents both in vitro and in vivo. Experimental design: We investigated the effect of BRCA2 deletion on PSMA expression in the castration sensitive human PC cell line LNCaP at the transcriptional and translational level and quantified the changes using saturation binding assays with [124I]-MSK-PSMA11. Using CRISPR-Cas9 and RNAi-based methods, we silenced BRCA2 in the castration sensitive cell line LNCaP and evaluated its effect on PSMA at the transcriptional and translational level. We carried out saturation binding assay using [124I]-MSK-PSMA11 to measure changes in cell surface PSMA receptor density. Results: BRCA2 knockout was achieved successfully using CRISPR-Cas9 based methods. Immunoblotting analysis revealed that BRCA2 loss resulted in a significant increase in PSMA levels when compared to control LNCaP cell line. Immunohistochemical analysis confirmed this obervation. Cell binding assays demonstrated that BRCA2 null LNCaP cell lines have about 5-6 fold higher uptake of the PET tracer [124I]-MSK-PSMA11. We will be conducting in vivo studies to demonstrate that BRCA2 deletion leads to a significant increase in PSMA signal in mice xenograft models. Conclusions: Our results indicate that BRCA2 silencing leads to significant upregulation of PSMA expression in PC cell lines, which can be imaged using a PSMA targeted PET tracer. These studies were partly supported by DOD-PCRP-Grant # W81XWH-19-1-0536 and PCF Young Investigator Award to Goutam Chakraborty. References: Chakraborty G et al. Clin Can Res 2019 DOI:10.1158/1078-0432.CCR-19-1570; Paschalis A et al. Eur Urol. 2019 Oct; 76(4): 469-478. Citation Format: Teja Kalidindi, Sang Gyu Lee, Heiko Schoder, Lina E. Jehanae, Rahim Hirani, Goutam Chakraborty, Philip W. Kantoff, Naga Vara Kishore Pillarsetty. Non-invasive imaging tool to predict BRCA2 silencing in the context of prostate cancer [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 1650.

Purpose: To compare the diagnostic and prognostic value of [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) and bone scans (BS) in the assessment of osseous lesions in patients with progressing prostate cancer. Experimental Design: In a prospective imaging trial, 43 patients underwent FDG-PET and BS prior to experimental therapies. Bone scan index (BSI) and standardized uptake value (SUV) on FDG-PET were recorded. Patients were followed until death (n = 36) or at least 5 years (n = 7). Imaging findings were correlated with survival. Results: Osseous lesions were detected in 39 patients on BS and 32 on FDG-PET (P = 0.01). Follow-up was available for 105 FDG-positive lesions, and 84 (80%) became positive on subsequent BS. Prognosis correlated inversely with SUV (median survival 14.4 versus 32.8 months if SUVmax > 6.10 versus ≤ 6.10; P = 0.002) and BSI (14.7 versus 28.2 months if BSI > 1.27 versus < 1.27; P = 0.004). Only SUV was an independent factor in multivariate analysis. Conclusion: This study of progressive prostate cancer confirms earlier work that BSI is a strong prognostic factor. Most FDG-only lesions at baseline become detectable on follow-up BS, suggesting their strong clinical relevance. FDG SUV is an independent prognostic factor and provides complementary prognostic information. Clin Cancer Res; 16(24); 6093–99. ©2010 AACR.

Experimental Design: Retrospective cohort study in 91 patients with prostate-specific antigen (PSA) relapse following prostatectomy, imaged with 2-[18F]fluoro-2-deoxyglucose positron emission tomography (FDG-PET) in a tertiary care cancer center between February 1997 and March 2003. Comparison was made with magnetic resonance imaging (n = 64), bone scan (n = 56), and computed tomography (n = 37). The standard of reference included biopsy or clinical and imaging follow-up. We calculated sensitivity and specificity of PET and correlated PET findings with PSA values, other clinical parameters, and conventional imaging, when available. Results: PET was true positive in 28 of 91 (31%) patients, showing isolated disease in the prostate bed (n = 3) or metastatic disease with (n = 2) or without (n = 23) simultaneous disease in the prostate bed. In detail, PET identified lesions in the prostate bed (n = 5, all true positives), bones (n = 22; 20 true positives, 2 false positives), lymph nodes (n = 7; 6 true positives, 1 likely false positive), and one liver metastasis. Mean PSA was higher in PET-positive than in PET-negative patients (9.5 ± 2.2 versus 2.1 ± 3.3 ng/mL). PSA of 2.4 ng/mL and PSA velocity of 1.3 ng/mL/y provided the best tradeoff between sensitivity (80%; 71%) and specificity (73%; 77%) of PET in a receiver operating curve analysis. Combination with other clinical parameters in a multivariate analysis did not improve disease prediction. There were only two patients in whom other imaging studies showed isolated local recurrence or metastatic disease. Conclusions: FDG-PET detected local or systemic disease in 31% of patients with PSA relapse referred for this test. There is a link to tumor burden and tumor biology in that the probability for disease detection increased with PSA levels.