Lamin Juwara

Phase I trial of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat shock protein inhibitor, administered twice weekly in patients with advanced malignancies

PURPOSE Phase I dose-escalation study to determine the toxicity and maximum tolerated dose (MTD) of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat shock protein 90 (Hsp90) inhibitor, administered on a twice weekly schedule in patients with advanced cancer. EXPERIMENTAL DESIGN 17-DMAG was administered as a 1- to 2-h infusion twice weekly in 4-week cycles. An accelerated titration design was followed until toxicity was observed, at which point standard dose-escalation proceeded. MTD was defined as the dose at which no more than one of the six patients experienced a dose-limiting toxicity (DLT). Pharmacokinetics were assessed, and Hsp70 mRNA, whose gene product is a chaperone previously shown to be upregulated following the inhibition of Hsp90, was measured in peripheral blood mononuclear cells (PBMCs). RESULTS A total of 31 patients received 92 courses of treatment. The MTD was 21mg/m(2)/d; 20 patients were enrolled at this dose level. Nine patients had stable disease for a median of 4 (range 2-22) months. Both C(max) and AUC increased proportionally with dose. The most common toxicities were grade 1 or 2 fatigue, anorexia, nausea, blurred vision and musculoskeletal pain. DLTs were peripheral neuropathy and renal dysfunction. Expression of Hsp70 mRNA in PBMCs was highly variable. CONCLUSION Twice-weekly i.v. infusion of 17-DMAG is well tolerated, and combination phase I studies are warranted.

Multihistology, Target-Driven Pilot Trial of Oral Topotecan as an Inhibitor of Hypoxia-Inducible Factor-1α in Advanced Solid Tumors

Purpose: Hypoxia-inducible factor 1 (HIF-1) α is frequently overexpressed in human tumors and is associated with angiogenesis and metastasis. Topotecan, a topoisomerase I inhibitor, has been shown to inhibit HIF-1α expression in preclinical models. We designed a pilot trial to measure HIF-1α inhibition in tumor biopsies from patients with advanced solid tumors overexpressing HIF-1α, after treatment with oral topotecan. Experimental Design: Topotecan was administered orally at 1.6 mg/m2 once daily for 5 days/week for 2 weeks, in 28-day cycles. Objectives were to determine inhibition of expression of HIF-1α and HIF-1 target genes in tumor; to assess tumor blood flow by dynamic contrast–enhanced magnetic resonance imaging (DCE-MRI); and to measure pharmacokinetics. Tumor biopsies were collected at baseline and during the second cycle of treatment. Results: Sixteen patients were enrolled. The dose of topotecan was reduced to 1.2 mg/m2/day due to myelosuppression. Seven patients had paired tumor biopsies. In 4 patients, HIF-1α nuclear staining became undetectable after treatment (7.5%–50% staining at baseline). Decreased levels of VEGF and GLUT-1 mRNA were measured in 4 patients; the changes were concordant with reduction in HIF-1α in 3 patients. Decreased tumor blood flow and permeability were observed by DCE-MRI in 7 of 10 patients after 1 cycle. One patient had a partial response accompanied by inhibition of HIF-1α in tumor and reduction in tumor blood flow on DCE-MRI. Conclusions: This multihistology, target assessment trial of a small molecule inhibitor of HIF-1α showed that topotecan could decrease HIF-1α expression in advanced solid tumors. Clin Cancer Res; 17(15); 5123–31. ©2011 AACR.

Phase I trial of vandetanib and bevacizumab evaluating the VEGF and EGF signal transduction pathways in adults with solid tumours and lymphomas

PURPOSE Inhibition of epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) pathways may result in synergistic antitumour activity. We designed a phase I study to evaluate the combination of vandetanib, an investigational agent with activity against EGF receptor and VEGF receptor 2, and bevacizumab, a monoclonal antibody against VEGF. EXPERIMENTAL DESIGN Patients with advanced solid tumours and lymphomas were enrolled. Objectives were to determine the safety and maximum tolerated dose of the combination, characterise pharmacokinetics, measure angiogenic marker changes in blood, and assess tumour blood flow using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Vandetanib was given orally once daily and bevacizumab intravenously once in every 3 weeks in 21-day cycles utilising a standard dose-escalation design. RESULTS Fifteen patients were enrolled, and a total of 94 cycles of therapy were administered. No protocol-defined dose-limiting toxicities were observed; due to toxicities associated with chronic dosing, hypertension, proteinuria, diarrhoea and anorexia, dose escalation was stopped at the second dose level. We observed one partial response and one minor response; 9 patients experienced stable disease. There were significant changes in plasma VEGF and placental-derived growth factor levels, and decreases in K(trans) and k(ep) were observed by DCE-MRI. CONCLUSION In this trial, we safely combined two targeted agents that cause dual blockade of the VEGF pathway, demonstrated preliminary evidence of clinical activity, and conducted correlative studies demonstrating anti-angiogenic effect. The recommended phase II dose was established as vandetanib 200 mg daily and bevacizumab 7.5 mg/kg every 3 weeks.

Clinical Activity of the γ-Secretase Inhibitor PF-03084014 in Adults With Desmoid Tumors (Aggressive Fibromatosis)

Purpose Desmoid tumors (aggressive fibromatosis) arise from connective tissue cells or fibroblasts. In general, they are slow growing and do not metastasize; however, locally aggressive desmoid tumors can cause severe morbidity and loss of function. Disease recurrence after surgery and/or radiation and diagnosis of multifocal desmoid tumors highlight the need to develop effective systemic treatments for this disease. In this study, we evaluate objective response rate after therapy with the γ-secretase inhibitor PF-03084014 in patients with recurrent, refractory, progressive desmoid tumors. Patients and Methods Seventeen patients with desmoid tumors received PF-03084014 150 mg orally twice a day in 3-week cycles. Response to treatment was evaluated at cycle 1 and every six cycles, that is, 18 weeks, by RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1. Patient-reported outcomes were measured at baseline and at every restaging visit by using the MD Anderson Symptoms Inventory. Archival tumor and blood samples were genotyped for somatic and germline mutations in APC and CTNNB1. Results Of 17 patients accrued to the study, 15 had mutations in APC or CTNNB1 genes. Sixteen patients (94%) were evaluable for response; five (29%) experienced a confirmed partial response and have been on study for more than 2 years. Another five patients with prolonged stable disease as their best response remain on study. Patient-reported outcomes confirmed clinician reporting that the investigational agent was well tolerated and, in subgroup analyses, participants who demonstrated partial response also experienced clinically meaningful and statistically significant improvements in symptom burden. Conclusion PF-03084014 was well tolerated and demonstrated promising clinical benefit in patients with refractory, progressive desmoid tumors who receive long-term treatment.

A Phase I Study of Ganetespib and Ziv‐Aflibercept in Patients with Advanced Carcinomas and Sarcomas

Abstract Lessons Learned. The combination of the antiangiogenic agent ziv‐aflibercept and the heat shock protein 90 inhibitor ganetespib was associated with several serious and unexpected adverse events and was not tolerable on the dosing schedule tested. Studies such as these emphasize the importance of considering overlapping toxicities when designing novel treatment combination regimens. Background. Although inhibition of angiogenesis is an effective strategy for cancer treatment, acquired resistance to antiangiogenic therapy is common. Heat shock protein 90 (Hsp90) is a molecular chaperone that regulates various oncogenic signaling pathways involved in acquired resistance and has been shown to play a role in angiogenesis. Combining an antiangiogenic agent with an Hsp90 inhibitor has therefore been proposed as a strategy for preventing resistance and improving antitumor activity. We conducted a single‐arm phase I study evaluating the combination of ziv‐aflibercept, an antiangiogenic drug, with the Hsp90 inhibitor ganetespib. Methods. Adult patients were eligible if they had recurrent or metastatic gastrointestinal carcinomas, nonsquamous non‐small cell lung carcinomas, urothelial carcinomas, or sarcomas that had progressed after at least one line of standard therapy. Ziv‐aflibercept was administered intravenously on days 1 and 15, and ganetespib was administered intravenously on days 1, 8, and 15, of each 28‐day cycle. Results. Five patients were treated with the combination. Although three patients achieved stable disease, study treatment was associated with several serious and unexpected adverse events. Conclusion. The dose escalation phase of this study was not completed, but the limited data obtained suggest that this combination may be too toxic when administered on this dosing schedule.

Abstract 4678: Pilot trial of talazoparib (BMN 673), an oral PARP inhibitor, in patients with advanced solid tumors carrying deleterious BRCA mutations

Inhibition of poly (ADP-ribose) polymerase (PARP) sensitizes tumor cells to DNA damage that would normally be repaired through the base excision repair pathway. PARP inhibitors are active clinically against BRCA-deficient ovarian cancers. The PARP inhibitor talazoparib produces cytotoxicity in human cancer cell lines and animal models of tumors that harbor mutations that compromise DNA repair pathways. In this study, single agent talazoparib (1000 µg/day) was administered to patients with deleterious BRCA1 or BRCA2 mutations and advanced solid tumors in 28 day cycles. The primary objective of the trial was to examine pharmacodynamic (PD) effects of talazoparib; the secondary objective was to determine response rate in patients whose tumors carry BRCA mutations. Mandatory paired tumor biopsies were obtained pre-treatment and 3-6 hrs post-treatment on cycle 1 day 8. Optional biopsies were collected at the time of progression. One core from each time point was analyzed for PARP inhibition by a validated ELISA assay while the other core was used for IFA analysis of γH2AX. A total of 9 patients (pts) were enrolled and treated before this trial was closed due to lack of drug availability: [prostate (3), ovarian (2), breast (2), uterine sarcoma (1), pancreatic (1)]. Median age was 63 (range: 33-73 yrs); male-to-female ratio was 4:5; and the median number of prior treatments was 6 (range: 1-12). All 9 pts were evaluable for PD endpoints. One pt progressed during the first cycle of treatment; 8 pts were evaluable for clinical response. Mean time on study for evaluable pts was 8 cycles (range: 2-18); 5 of 8 (62%) pts experienced a documented partial responses [ovarian (2), prostate (2), breast (1)] lasting between 4 and 12 cycles (median: 6 cycles). Two pts had stable disease for 4 to 6 cycles, and one progressed after 2 cycles. The agent was well tolerated; the most frequent adverse events were hematologic including grade (gr) 4 anemia (1) and thrombocytopenia (1), and gr 3 anemia (2), neutropenia (1), lymphopenia (1). Decreases in PAR levels (>75%) were observed in all cycle 1 day 8 biopsy pairs, documenting a primary PD effect. Increased γH2AX expression was observed for 4/6 pts in post-dose biopsies; pre-treatment γH2AX levels, measured as %Nuclear Associated Protein (NAP), increased from a mean ± SD of 1.33 ± 1.08 to a post-treatment %NAP mean of 5.60 ± 0.78; (p=0.018), supporting a role for drug-enhanced DNA double strand breaks in the mechanism of action of talazoparib for BRCA mutant tumors. In summary, talazoparib demonstrated significant clinical activity as a single agent in patients with BRCA-deficient tumors and produced substantial reductions in tumor PAR levels in matched pre and post-treatment tumor biopsies. Citation Format: Robert S. Meehan, Alice P. Chen, Geraldine O’Sullivan Coyne, Shivaani Kummar, Jiuping Ji, Rasa Vilimas, Lamin Juwara, Robert J. Kinders, Katherine Ferry-Galow, Deborah Wilsker, Yiping Zhang, Angie B. Dull, Tony Navas, Lihua Wang, Ralph E. Parchment, James H. Doroshow. Pilot trial of talazoparib (BMN 673), an oral PARP inhibitor, in patients with advanced solid tumors carrying deleterious BRCA mutations [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 4678. doi:10.1158/1538-7445.AM2017-4678

Abstract 3718: A Phase II Study of Sorafenib plus Cetuximab in colorectal cancer (CRC) expressing epidermal growth factor receptor (EGFR) and mutated K-ras

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Background: The presence of K-ras mutation predicts for a lack of response to EGFR-directed therapies in CRC. We hypothesized that a drug capable of inhibiting Raf kinase, which is downstream of Ras, could restore tumor sensitivity to cetuximab. We conducted a Phase II single-arm optimal two-stage design trial of cetuximab, a monoclonal antibody directed against EGFR, in combination with sorafenib, a small molecule inhibitor of VEGFR2 and Raf kinase, in patients with EGFR-positive (+) CRC bearing K-ras mutations. Trial Design: Objectives were to determine clinical benefit rate (CBR) (CR+PR+SD for 4 months) and PFS. Eligible patients were ≥ 18 years old and had histologically documented EGFR+ metastatic CRC bearing K-ras mutations which had recurred or progressed following at least one prior chemotherapy regimen; measurable disease; ECOG PS 0-1; adequate bone marrow, hepatic and renal function. Patients previously treated with an EGFR inhibitor were excluded. Cetuximab was given IV at 400 mg/m2 initially as a loading dose on week 1, followed by 250 mg/m2 weekly, in 28-day cycles. Sorafenib was self-administered orally at 400 mg BID. Radiologic assessment was performed at baseline and every 2 cycles; response was determined based on RECIST criteria. Changes in tumor vascularity were evaluated by dynamic contrast-enhanced MRI (DCE-MRI) at baseline and after 2 cycles. Results: A total of 9 patients received at least 2 cycles of therapy and were evaluable for response. The median age was 51 years (range 21-81 years), and all patients had an ECOG PS of 1 and had received prior FU, oxaliplatin, irinotecan, and bevacizumab. Rash, electrolyte abnormalities, hypertension, and diarrhea were the most common toxicities. Grade 2 and 3 toxicities (number of patients in parentheses) were hypophosphatemia (5), hypokalemia (1), hypomagnesemia (1), acneiform rash (2), hand-foot syndrome (1), diarrhea (3), transaminitis (2), hyperbilirubinemia (1), lymphopenia (6), hypertension (1), anemia (1), and hypoalbuminemia (4). The only grade 4 events were lymphopenia (1) and hypokalemia (1). Although no patients had objective responses, 3 patients had stable disease for 6, 6 and 4 months respectively. DCE-MRI results showed reduction in the parameters of permeability, with decrease in ktrans and kep values. Quantitative biomarker analysis with determination of plasma angiogenic factors is ongoing. Conclusions: Sorafenib in combination with cetuximab is well tolerated in CRC patients and was associated with disease stabilization in 3 of 9 patients with EGFR+ CRC bearing K-ras mutations. Sorafenib plus cetuximab may have a role in the treatment of patients with CRC bearing Kras mutations. We have met the response goals for the first stage of the trial, and accrual continues for the second stage. Funded by NCI Contract No. HHSN261200800001E. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3718.