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Purpose: Soft-tissue sarcomas (STS) are a rare, heterogeneous group of mesenchymal tumors. For decades the mainstay of treatment for advanced, unresectable STS has been palliative chemotherapy. High levels of activated MET receptor have been reported in various sarcoma cell lines, together with elevated vascular endothelial growth factor (VEGF) levels in patients with STS, suggesting that dual targeting of the VEGF and MET pathways with the multi-receptor tyrosine kinase inhibitor cabozantinib would result in clinical benefit in this population. Patients and Methods: We performed an open-label, multi-institution, single-arm phase II trial of single-agent cabozantinib in adult patients with advanced STS and progressive disease after at least 1 standard line of systemic therapy. Patients received 60 mg oral cabozantinib once daily in 28-day cycles, and dual primary endpoints of overall response rate and 6-month progression-free survival (PFS) were assessed. Changes in several circulating biomarkers were assessed as secondary endpoints. Results: Six (11.1%; 95% CI, 4.2%–22.6%) of the 54 evaluable patients enrolled experienced objective responses (all partial responses). Six-month PFS was 49.3% (95% CI, 36.2%–67.3%), with a median time on study of 4 cycles (range, 1–99). The most common grade 3/4 adverse events were hypertension (7.4%) and neutropenia (16.7%). Patients' levels of circulating hepatocyte growth factor (HGF), soluble MET, and VEGF-A generally increased after a cycle of therapy, while soluble VEGFR2 levels decreased, regardless of clinical outcome. Conclusions: Cabozantinib single-agent antitumor activity was observed in patients with selected STS histologic subtypes (alveolar soft-part sarcoma, undifferentiated pleomorphic sarcoma, extraskeletal myxoid chondrosarcoma, and leiomyosarcoma) highlighting the biomolecular diversity of STS.

Purpose Following promising responses to the DNA methyltransferase (DNMT) inhibitor 5-fluoro-2′-deoxycytidine (FdCyd) combined with tetrahydrouridine (THU) in phase 1 testing, we initiated a non-randomized phase 2 study to assess response to this combination in patients with advanced solid tumor types for which tumor suppressor gene methylation is potentially prognostic. To obtain pharmacodynamic evidence for DNMT inhibition by FdCyd, we developed a novel method for detecting expression of tumor suppressor protein p16/INK4A in circulating tumor cells (CTCs). Methods Patients in histology-specific strata (breast, head and neck [H&N], or non-small cell lung cancers [NSCLC] or urothelial transitional cell carcinoma) were administered FdCyd (100 mg/m2) and THU (350 mg/m2) intravenously 5 days/week for 2 weeks, in 28-day cycles, and progression-free survival (PFS) rate and objective response rate (ORR) were evaluated. Blood specimens were collected for CTC analysis. Results Ninety-three eligible patients were enrolled (29 breast, 21 H&N, 25 NSCLC, and 18 urothelial). There were three partial responses. All strata were terminated early due to insufficient responses (H&N, NSCLC) or slow accrual (breast, urothelial). However, the preliminary 4-month PFS rate (42%) in the urothelial stratum exceeded the predefined goal—though the ORR (5.6%) did not. An increase in the proportion of p16-expressing cytokeratin-positive CTCs was detected in 69% of patients evaluable for clinical and CTC response, but was not significantly associated with clinical response. Conclusion Further study of FdCyd + THU is potentially warranted in urothelial carcinoma but not NSCLC or breast or H&N cancer. Increase in the proportion of p16-expressing cytokeratin-positive CTCs is a pharmacodynamic marker of FdCyd target engagement.

BACKGROUND: Molecular chaperone targeting has shown promise as a therapeutic approach in human cancers of various histologies and genetic backgrounds. The purine-scaffold inhibitor PU-H71 (NSC 750424), selective for Hsp90 in epichaperome networks, has demonstrated antitumor activity in multiple preclinical cancer models. The present study was a first in-human trial of PU-H71 aimed at establishing its safety and tolerability and characterizing its pharmacokinetic (PK) profile on a weekly administration schedule in human subjects with solid tumors refractory to standard treatments. METHODS: PU-H71 was administered intravenously over 1 h on days 1 and 8 of 21-day cycles in patients with refractory solid tumors. Dose escalation followed a modified accelerated design. Blood and urine were collected during cycles 1 and 2 for pharmacokinetics analysis. RESULTS: Seventeen patients were enrolled in this trial. Grade 2 and 3 adverse events were observed but no dose limiting toxicities occurred, thus the human maximum tolerated dose was not determined. The mean terminal half-life (T(1/2)) was 8.4 ± 3.6 h, with no dependency to dose level. A pathway for the metabolic disposal of PU-H71 in humans was derived from microsome studies. Fourteen patients were also evaluable for clinical response; 6 (35%) achieved a best response of stable disease for >2 cycles, with 2 patients remaining on study for 6 cycles. The study closed prematurely due to discontinuation of drug supply. CONCLUSIONS: PU-H71 was well tolerated at the doses administered during this study (10 to 470 mg/m(2)/day), with no dose limiting toxicities.

Background: We initiated the systematic NCI-ALMANAC in vitro combination drug screen of FDA-approved anticancer drugs in the NCI-60 tumor cell line panel to explore novel and effective drug combinations (Holbeck et al., Cancer Res 2017). In this screen and in preclinical xenograft models, the BCR-ABL kinase inhibitor nilotinib demonstrated greater-than-additive activity in combination with the anti-tubulin agent paclitaxel. Additionally, recent preclinical findings suggest a reduced incidence of peripheral neuropathy for this combination relative to paclitaxel monotherapy (Leblanc et al., J Clin Invest 2018). We are performing a phase 1 study to establish the safety, tolerability, and maximum tolerated dose (MTD) of this combination in patients (pts) with advanced solid tumors, and to examine the pharmacokinetic (PK) and pharmacodynamic (PD) effects of the combination to better understand the mechanism of synergy. Materials and Methods: Nilotinib was given orally twice-daily (BID), while paclitaxel was administered intravenously on days 1, 8, and 15 of each 28-day cycle. A 1- or 2-day paclitaxel-only run-in during the first cycle enabled comparison of the PK and PD effects of the combination vs. single-agent paclitaxel. Dose-limiting toxicities (DLTs) were assessed during cycle 1, and response was evaluated by CT per RECIST 1.1. Results: Thirty pts have been enrolled to date. The MTD was 300 mg nilotinib BID and 80 mg/m2 paclitaxel given on days 1, 8, and 15; DLTs were grade 4 rash and grade 3 myelosuppression. Only 2 pts (7%) have experienced grade 2 peripheral neuropathy, no grade ≥3 neuropathy events occurred. Of the 24 pts assessable for response to date, there are 4 confirmed partial responses (PRs; 17%, 1 pt with endometrial cancer, 1pt with anal cancer and 2 pts with granulosa cell of the ovary) and 12 pts with a best response of stable disease (SD; 50%), including 6 pts with SD for ≥ 8 cycles. Mean time on study to date is 8.7 months (range: 2 – 41 months). Three of 4 responding pts had undergone prior paclitaxel-based therapy and experienced a best response of only SD (1 pt) or progressive disease (2 pts) to carboplatin/paclitaxel or paclitaxel monotherapy, respectively. PK data demonstrate dose-dependent plasma paclitaxel concentrations (for 60 vs. 80 mg/m2 paclitaxel), and no substantial effects of nilotinib on paclitaxel plasma concentrations. Conclusions: The combination of nilotinib and paclitaxel is well-tolerated. Consistent with recent preclinical findings, no grade ≥ 3 peripheral neuropathy has been observed, as compared to rates of 8-30% in prior studies of 80-100 mg/m2 weekly paclitaxel monotherapy in pts with metastatic breast cancer (Rivera and Cianfrocca, Cancer Chemother Pharmacol 2015). PK data indicate dose-dependent plasma paclitaxel concentrations, with no substantial nilotinib-induced changes in plasma paclitaxel levels. Preliminary response data are promising, especially considering the PRs observed in pts who had previously been unresponsive to paclitaxel therapy. Accrual to the expansion cohort and PD analyses of circulating tumor cells and tumor biopsy specimens are ongoing. Citation Format: Geraldine O'Sullivan Coyne, Shivaani Kummar, Jennifer Zlott, Lamin Juwara, Naoko Takebe, Murielle Hogu, Larry Anderson, Jerry Collins, Richard Piekarz, Howard Streicher, Elad Sharon, Arjun Mittra, Sabrina Khan, Brandon Miller, Tony Navas, Apurva Srivastava, Ralph Parchment, Laurence Rubinstein, James H Doroshow, Alice P Chen. Tolerability and antitumor activity of paclitaxel is improved by the addition of nilotinib in patients with refractory solid tumors [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 C008. doi:10.1158/1535-7163.TARG-19-C008

Background: The base excisional repair (BER) pathway plays an important role in the development of resistance to alkylating agents. TRC102 (methoxyamine HCL) inhibits BER by binding apurinic/apyrimidinic sites, which increases temozolomide (TMZ)-induced DNA strand breaks and apoptosis. We conducted a multihistology phase I/II trial of TRC102 in combination with TMZ in patients (pts) with refractory solid tumors (NCT01851369); here we report the clinical activity of this combination in the phase II refractory colorectal carcinoma (CRC) cohort. The phase I portion of the study demonstrated anemia to be the major dose limiting toxicity of this combination; the recommended phase II doses (RP2D) for the combination were: 125 mg TRC 102 + 150 mg/m2 TMZ (PO, D1-5 of 28-day cycles). The expanded phase II trial utilized a 3-arm Simon 2-stage design based on objective responses documented during the phase I portion of the study (CRC, NSCLC, and granulosa cell ovarian cancer). Methods: Phase II pts were treated at the RP2D, except that pts with BSA < 1.6 m2 received 100 mg of TRC102. Eligibility for the CRC cohort included pts with recurrent, metastatic, histologically confirmed colorectal adenocarcinoma after ≥ 2 lines of therapy, adequate organ function, and an ECOG performance status (PS) ≤ 1. Overall response rate (ORR) was defined as a partial response (PR) or a complete response (CR), per RECIST 1.1 criteria. Results: During the phase I trial, one pt with KRAS mutant CRC experienced a sustained PR of 21 cycles (maximum 70% decrease by RECIST). This pt decided to stop treatment due to travel constraints, but at 17 months off treatment had not progressed. Based on this response, 16 pts were enrolled in the CRC cohort of the phase II trial (3 rectal, 13 colon), all heavily pretreated (median: 6 lines of prior therapy, range: 3-14). Median pt age was 64 years (range: 46-80 years); all had an ECOG PS of 1. Median time on study was 2 cycles (range: 1 to 5 cycles) including 5 pts who came off study for early clinical progression. ORR for this cohort was 6% (1 PR). Nine pts had KRAS mutant disease, including the partial responder, who also was the only pt (of the 10 tested by tumor IHC) with MGMT-negative disease. Grade 3 and 4 protocol treatment-related toxicities included thrombocytopenia (2 pts), hemolysis (1 pt), and diarrhea (1 pt). No pts discontinued the protocol because of toxicity and only 1 pt required dose reduction (thrombocytopenia). Conclusions: Despite a promising phase I result from a pt with CRC, a phase II study of combined TRC102 and TMZ treatment in patients with metastatic colon or rectal adenocarcinoma displayed an ORR of 6%. Assessing tumor MGMT status may help identify pts who could benefit from this combination and pharmacodynamic studies are underway to assess drug activity in responding and non-responding patients. Supported in part by NCI Contract HHSN261200800001E. Citation Format: Geraldine OSullivan Coyne, Cecilia Monge Bonilla, Jennifer Zlott, Naoko Takebe, Robert Meehan, Lamin Juwara, Richard Piekarz, Laurence Rubinstein, Deborah F. Wilsker, Robert J. Kinders, Ralph E. Parchment, Shahanawaz Jiwani, Shivaani Kumar, James H. Doroshow, Alice P. Chen. A Phase II trial of TRC102 (methoxyamine HCl) in combination with temozolomide in patients with relapsed metastatic colorectal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-293.

Background: Modulation of BRCA1 and ATR has been postulated as an activation mechanism of checkpoint 1 (Chk1), which in turn triggers homologous recombination repair through modulation of BRCA2-Rad51, and the initiation of cell cycle checkpoints through phosphorylation and activation of Wee1. Wee1 is a tyrosine kinase implicated in the inhibitory phosphorylation of cyclin-dependent kinase 1 (CDK1/CDC2)-bound cyclin B, resulting in G2 cell cycle arrest in response to DNA damage. AZD1775 is a first-in-class selective inhibitor of Wee1 kinase that directly prevents phosphorylation of CDC2 at Tyr15. Model data show single-agent antitumor activity in multiple cancer cell lines across the NCI-60 and in both p53 intact and deficient tumor xenografts. We are conducting a phase I trial of AZD1775 in patients (pts) with refractory solid tumors, both with and without germline BRCA1/2 mutations (BRCA+), evaluating two different dosing schedules. We have previously reported on initial antitumor activity and proof-of-mechanism (Do et al, J Clin Oncol. 2015). This abstract reports the efficacy seen in the BRCA+ population. Methods: AZD1775 was administered orally twice daily (BID) for 5 doses [D1-3 and 8-10, Cohort A (A)] or once daily for 5 days [D1-5 and 8-12, Cohort B (B)] during weeks 1 and 2 of a 21-day cycle; 3+3 design. Primary objectives: establish safety, tolerability and PK of AZD1775. Secondary objectives: determine the effect of AZD1775 on markers of DNA damage and apoptosis in tumor tissue/circulating tumor cells, and antitumor activity. Dose-limiting toxicity (DLT) was determined during Cycle 1. Response defined by RECIST 1.1 on CT. Results: A total of 17 BRCA+ pts have enrolled; 9 pts on A (one pt withdrew for other therapy), and 8 pts on B. Nine pts with BRCA1, 7 pts with BRCA2: ovarian (9 pts), breast (2), pancreas (1), prostate (1), Fallopian tube (1), and peritoneal (1) cancer. Partial responses (PR) were confirmed on 2/8 pts (25%) in A with BRCA1 papillary serous ovarian cancer and squamous cell carcinoma of tongue. Two additional PRs (25%) were confirmed in BRCA1 serous ovarian cancer pts in B. Two further BRCA1 ovarian pts trended near PR. All 4 responders received prior platinum therapy; 3/3 ovarian cancer pts received and responded to prior PARP inhibitor therapy. No differences were noted in severity or rate of toxicity in pts with/without BRCA+: common grade 3/4 toxicities include anemia (6 pts, 37%), lymphopenia (5, 31%), neutropenia (4, 25%), and thrombocytopenia (3, 18%), occurring in responders and nonresponders. Conclusions: AZD1775 has single-agent antitumor activity in a BRCA deficient population, especially BRCA1. Responses were observed in pts with prior exposure to platinum and a PARP inhibitor. Additional accrual on a safety expansion cohort is ongoing, and assessment of PD biomarkers is planned for paired biopsies (NCT01748825). Citation Format: Geraldine OSullivan Coyne, Shivaani Kummar, Naoko Takebe, Khanh Tu Do, Robert Meehan, Richard Piekarz, Jennifer Zlott, Lamin Juwara, Mary Quinn, Elad Sharon, Howard Streicher, Lawrence Rubinstein, Chana Levine, James H. Doroshow, Alice P. Chen. Single agent AZD 1775, a Wee1 inhibitor, shows activity in BRCA deficient patients [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 B079.

Background: Base excision repair (BER), one of the pathways of DNA damage repair, has been implicated in chemoresistance. TRC102 acts through a novel mechanism to inhibit BER and cause DNA strand breaks, potentiating the antitumor activity of TMZ in preclinical models. We conducted a phase I trial of TRC102 in combination with TMZ to determine the safety, tolerability, and maximum tolerated dose of the combination; to evaluate the pharmacokinetics (PK) of each agent alone and in combination; and to assess DNA damage response (percent nuclear area of γH2AX foci) in circulating tumor cells (CTCs). Methods: Eligible pts were required to have refractory advanced solid tumors that had progressed following standard therapy; ≥ 18 yrs of age; ECOG PS 0-2; and adequate organ function. TRC102 and TMZ were administered orally once daily, D1-5 of q28d cycles; Starting dose level (DL 1) was TRC102 25 mg and TMZ 125mg/m2. Accrual to DL6 (TRC102 125 mg; TMZ 150 mg/m2) is ongoing. CTCs were obtained during C1 and on C2D1. Blood samples for PK analysis were obtained during C1. Results: Twenty pts have been enrolled to date; median age 59 yrs (range 45-78 yrs); median # of prior therapies: 3.5 (1-9); Dx: GI (6), H&N (4), breast (3), GYN (3), lung (2), soft tissue sarcoma (2). Fourteen pts are evaluable for response; 2 partial responses by RECIST have been observed to date (≥ 6 cycles; NSCLC and granulosa cell tumor of the ovary). Grade 3/4 toxicities (#pts): neutropenia (2), thrombocytopenia (1), lymphopenia (1), anemia (1), leucopenia (1), hypophosphatemia (1). PK in combination was similar to single agent PK reported for both drugs, with no evidence of a PK interaction. TRC102 levels required for preclinical activity (50ng/mL) were achieved at DL1. T1/2 of TRC102 was 26 hr. CTC analysis is ongoing. Conclusions: Combination of TRC102 with TMZ is well tolerated and clinical activity was observed with 2 partial responses to date. MTD has not been reached; accrual is ongoing. Paired tumor biopsies to assess for evidence of DNA damage response and apoptosis are planned at the MTD in the expansion phase. Citation Format: Woondong Jeong, Khanh Do, Alice Chen, Jennifer Zlott, Lamin Juwara, Yvonne Horneffer, Robert Kinders, Lihua Wang, Priya Balasubramanian, Larry Anderson, Elad Sharon, Howard Streicher, Richard Piekarz, Barbara Conley, Jerry Collins, James H. Doroshow, Shivaani Kummar. A phase I trial of oral TRC102 (methoxyamine HCl) in combination with temozolomide (TMZ) in patients with relapsed solid tumors. [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 CT316. doi:10.1158/1538-7445.AM2015-CT316