Citations

Abstract Background: Breast cancer recurrence has been shown to differ based upon CYP2D6 genotype and endoxifen (Endx) exposure following treatment with tamoxifen (TAM) in the adjuvant setting. The average Endx Css is 29 nM (range, 2-80 nM) in TAM treated patients at a dose of 20 mg/day. Administration of Endx itself to patients is predicted to provide adequate, consistent, active drug levels in all treated patients, resulting in clinical benefit. As part of two phase 1 trials of oral Endx to determine the safety, tolerability, and MTD, we characterized the pharmacokinetics and in vivo metabolism of Endx. Methods: Patients were given escalating daily oral doses of Endx (28 day cycle) over the dose range of 20 - 160 mg/day in Phase I trials at the Mayo Clinic and NCI. Pharmacokinetics sampling was performed on days 1, 7, 14 and 28, and prior to subsequent cycles. Endx plasma concentrations and metabolite profiles were determined by HPLC and LC/MS/MS. Results: 44 patients with ECOG PS 0-1 have been enrolled to date encompassing 8 dose levels in the Mayo (25 women with AI refractory MBC; median age 58 yrs, range 41-83 yrs) and NCI (19 women with ovary (9), breast (4), desmoid (2), fallopian tube (2), endometrial cancer (2); median age 64 yrs, range 43-75 yrs) studies. Day 1 Endx peak concentrations (Cmax) were reached 4h after the Endx oral dose and mean values of Cmax, C24h, and AUC0-24h increased in proportion to dose. Css was achieved on day 7 and 3.5-fold accumulation (t1/2= 50.5 h) was observed on day 28. At the starting dose ( 20 mg/day) and highest dose level (160 mg/day), Endx Css values of 146 ng/ml (390 nM) and 1950 ng/ml (5200 nM), respectively, were achieved and maintained throughout the 28-day treatment. Endx Css values remained unchanged following continuous dosing for 8-10 months. The mean apparent steady-state clearance was 6.2 L/h. We also characterized the Endx metabolite profile in patient plasma and urine. Metabolites detected in plasma include nor-Endx, N-hydroxy-Endx, Endx-catechol, methoxy-Endx catechol, and Endx-glucuronide, and appear in amounts much lower compared to Endx. Like the parent drug, metabolites accumulated in plasma over the 28-day cycle. Characterization of the pharmacokinetics of Nor-Endx, a putative aromatase inhibitor, is ongoing and will be presented. Conclusion: In these ongoing Phase I studies, daily administration of Endx is well tolerated with Css consistently above those obtained following administration of standard dose tamoxifen. In the Mayo study, expansion at 20 and 100 mg/day has commenced to perform translational studies and further characterize Endx PK. In the NCI study, dose escalation continues to establish the maximum tolerated dose. Supported in part by R01CA 133049, U01 CA69912, P30CA 15083, P50CA 116201 and NCI Contracts CM52206 and HHSN261201100014C. Citation Format: Joel M. Reid, Matthew P. Goetz, Shivaani Kumar, Renee M. McGovern, Sarah A. Buhrow, Stephanie L. Safgren, Vera J. Suman, Travis J. Docktor, Charles Erlichman, Howard Streicher, James H. Doroshow, Jerry Collins, Matthew M. Ames. Pharmacokinetics and in vivo metabolism of Z-endoxifen: Results from two phase I studies in women with ER+ breast cancer, gynecologic malignancies and desmoids. [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 4631. doi:10.1158/1538-7445.AM2014-4631

Purpose There are few effective therapies for pancreatic neuroendocrine tumors (PNETs). Recent placebo-controlled phase III trials of the mammalian target of rapamycin (mTOR) inhibitor everolimus and the vascular endothelial growth factor (VEGF)/platelet-derived growth factor receptor inhibitor sunitinib have noted improved progression-free survival (PFS). Preclinical studies have suggested enhanced antitumor effects with combined mTOR and VEGF pathway–targeted therapy. We conducted a clinical trial to evaluate combination therapy against these targets in PNETs. Patients and Methods We conducted a two-stage single-arm phase II trial of the mTOR inhibitor temsirolimus 25 mg intravenously (IV) once per week and the VEGF-A monoclonal antibody bevacizumab 10 mg/kg IV once every 2 weeks in patients with well or moderately differentiated PNETs and progressive disease by RECIST within 7 months of study entry. Coprimary end points were tumor response rate and 6-month PFS. Results A total of 58 patients were enrolled, and 56 patients were eligible for response assessment. Confirmed response rate (RR) was 41% (23 of 56 patients). PFS at 6 months was 79% (44 of 56). Median PFS was 13.2 months (95% CI, 11.2 to 16.6). Median overall survival was 34 months (95% CI, 27.1 to not reached). For evaluable patients, the most common grade 3 to 4 adverse events attributed to therapy were hypertension (21%), fatigue (16%), lymphopenia (14%), and hyperglycemia (14%). Conclusion The combination of temsirolimus and bevacizumab had substantial activity and reasonable tolerability in a multicenter phase II trial, with RR of 41%, well in excess of single targeted agents in patients with progressive PNETs. Six-month PFS was a notable 79% in a population of patients with disease progression by RECIST criteria within 7 months of study entry. On the basis of this trial, continued evaluation of combination mTOR and VEGF pathway inhibitors is warranted.

Key Points Dinaciclib is a novel cdk inhibitor that demonstrates single agent activity in myeloma. Dinaciclib has a safety profile that is easily manageable.

Abstract Background: NPC is endemic to Asia and over 40% of cases harbor PIK3CA amplification. MK2206 is an allosteric AKT inhibitor with activity in NPC in vitro. Methods: Pts who had progressed after palliative chemotherapy (chemo) for metastatic or recurrent NPC, received oral MK-2206 at 200 mg on Days 1, 8, 15 & 22 of each 28-day cycle until disease progression. Plasma samples were collected at serial time points during cycle 1 for EBV DNA analysis, archived tumor samples were collected where feasible. The primary dual endpoints (2-stage design) consisted of RECIST-defined tumor response rate (RR) and 6-month (m) progression-free survival (PFS) rate. Secondary endpoints were overall survival (OS), PFS and adverse events (AEs). Results: Of the 21 pts enrolled, the median age was 47 years (range: 32-67), 91% were male, 81% had prior radiotherapy and 81% had > 1 prior line of palliative chemo. At the time of analysis, 20 out of 21 pts have ended treatment. The best responses were: 1 partial response (PR, 5%) lasting 4 ms; 10 stable disease (SD, 50%), 9 progressive disease (PD, 45%). The 6-m PFS rate was 38.9% (95% CI: 18.1-59.3%) and median PFS was 2.7 ms (95% CI: 0.9-7.2 ms). The 6-m OS rate was 67.9% (95% CI: 41.8-84.1%) and median survival has not been reached. In 7 pts who had SD more than or equal to 6 ms, the duration of treatment ranged from 6.4-13.9 ms. Of the 21 pts evaluable for AEs, 12 pts (57%) had at least one grade 3 AE [[Unable to Display Character: –]] macular rash (6 pts - 29%), dysphagia (2 pts - 10%), hyperglycemia (2 pts - 10%) (see Table 1). The tumor samples of 7 pts were analyzed by FISH; 3 showed PIK3CA amplification, including 1 pt with chromosome 3 polysomy. Amongst these pts, 1 had SD more than 6ms, 1 had SD more than 12 ms, and 1 is still on treatment. Pts who had SD less than 6 m or PD did not have PIK3CA amplification. Conclusions: MK2206 is well tolerated and has signs of activity in unselected pts with NPC. Preliminary results suggest that PIK3CA amplification may be related to prolonged disease stabilization from MK2206, and analysis for other PIK3CA gene alterations in more samples will be undertaken. Result of the plasma EBV DNA result will be presented. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B273. Citation Format: Brigette B. Ma, Boon Cher Goh, Wan Teck Lim, Eng Huat Tan, Gilberto de Lima Lopes, Edwin P. Hui, Ann D. King, Kwok Wai Lo, Herbert Loong, Leung Li, Nathan Foster, Michael Kam, Sing Fai Leung, Charles Erlichman, Anthony TC Chan. Multicenter Phase II study of MK-2206 in previously treated patients (pts) with recurrent and metastatic nasopharyngeal carcinoma (NPC): Mayo Clinic Phase II Consortium (Protocol: MC1079). [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 B273.

Abstract Background: In AI refractory MBC, TAM anti-tumor activity is limited (median PFS 4.5 months). In patients (pts) receiving TAM in the adjuvant and metastatic setting, breast cancer recurrence has been shown to differ based upon CYP2D6 genotype and Endx exposure. In collaboration with NCI, Z-Endx (NSC #750393) was synthesized and preclinical pharmacology studies demonstrated that oral Z- Endx resulted in > 20 fold Endx exposure compared to an equivalent dose of TAM and significantly greater anti-tumor activity than TAM in AI sensitive and resistant MCF7 xenografts. We conducted a phase I study of Z-Endx in women with ER+, AI refractory MBC to identify dose-limiting toxicities (DLT), a maximum tolerated dose (MTD) and a dose associated with steady state concentrations (Css) of ≥ 2 uM, based on the IC50 of recently identified Endx substrates: PKC and PI3K. Methods: Pts were enrolled to an accelerated titration schedule (2 pts/dose level) until moderate toxicity or DLT, and then to a 3+3 design. Z-Endx was administered orally once daily (28 day cycle). Eye exams were performed at baseline, end of cycle 2, and after 6 cycles. PK was performed on days 1-2, 3, 7, 14, and 28, and prior to subsequent cycles. Results: 23 women with AI refractory MBC (median 56 yrs, range 41-83) received Z-Endx once daily encompassing 7 dose levels (Table 1). The median number of prior chemotherapies and hormonal therapies in the metastatic setting were 2 and 2, respectively. Dose escalation continues at 160 mg/day and the MTD has yet to be determined. Cmax and AUC increased in a dose-dependent manner. A 20 and 100 mg/day dose yields Css of 0.39 and 2.48 uM, respectively. Significant anti-tumor activity was observed including 1 pt (100 mg/day) with a PR lasting 225 days; 1 pt (80 mg/day) with a 30% reduction in tumor size (PFS 169 days) and 2 pts (60 and 80 mg/day) with stable disease for >270 days. No eye toxicity was observed. Conclusions: In women with AI refractory MBC, the MTD of Z-Endx HCl has not been determined but Endx Css concentrations of > 2 uM and substantial anti-tumor activity has been observed. Following completion of the 160 mg/day dose, expansion at 20 and 100 mg/day will commence to perform translational studies and further characterize Endx pk. A randomized phase II examining two different doses of Z-Endx is planned in AI refractory MBC. Supported in part by CA 133049, CA69912, CA15083, CA116201, and CA15083. Table 1Dose Level (mg/day)Number of Treatment CyclesModerate or Severe Toxicities ReportedTumor ResponseProgression-free Survival (days)28 day Z-Endx Css (uM) 20 (n = 2)2; 3Gr 2 hot flashes (1 pt)----60; 850.39 40 (n = 2)2; 6noneStable (1 pt)61; 1670.66 60 (n = 6)1; 2; 2; 5; 8; 14Gr 4 Triglycerides (1 pt);Gr 3 thromboembolic event (1 pt); Gr 2 hot flashes, anemia, and hypoalbuminemia (1 pt)Stable (3 pts)125+; 56; 57; 132; 232; 4331.01 80 (n = 3)4; 6; 10Gr 2 hot flashesStable (3 pts)113; 169; 2961.61 100 (n = 3)1; 2; 8Gr 2 nausea (1 pt); Gr 2 irritability (1 pt)PR (1 pt)30; 56; 2252.48 120 (n = 3)1; 2; 4Gr 2 hypersomnia, paresthesia, and peripheral sensory neuropathy (1 pt)—39; 54; 1082.18 * Bold face toxicities occurred during cycle 1 Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD3-4.

AbstractSrc tyrosine kinases are overexpressed in pancreatic cancers, and the oral Src inhibitor saracatinib has shown antitumor activity in preclinical models of pancreas cancer. We performed a CTEP‐sponsored Phase II clinical trial of saracatinib in previously treated pancreas cancer patients, with a primary endpoint of 6‐month survival. A Simon MinMax two‐stage phase II design was used. Saracatinib (175 mg/day) was administered orally continuously in 28‐day cycles. In the unselected portion of the study, 18 patients were evaluable. Only two (11%) patients survived for at least 6 months, and three 6‐month survivors were required to move to second stage of study as originally designed. The study was amended as a biomarker‐driven trial (leucine rich repeat containing protein 19 [LRRC19] > insulin‐like growth factor‐binding protein 2 [IGFBP2] “top scoring pairs” polymerase chain reaction [PCR] assay, and PIK3CA mutant) based on preclinical data in a human pancreas tumor explant model. In the biomarker study, archival tumor tissue or fresh tumor biopsies were tested. Biomarker‐positive patients were eligible for the study. Only one patient was PIK3CA mutant in a 3′ untranslated region (UTR) portion of the gene. This patient was enrolled in the study and failed to meet the 6‐month survival endpoint. As the frequency of biomarker‐positive patients was very low (<3%), the study was closed. Although we were unable to conclude whether enriching for a subset of second/third line pancreatic cancer patients treated with a Src inhibitor based on a biomarker would improve 6‐month survival, we demonstrate that testing pancreatic tumor samples for a biomarker‐driven, multicenter study in metastatic pancreas cancer is feasible.

Abstract Background: Based upon preclinical synergy and prior phase 1 study results, the clinical efficacy of flavopiridol combined with cisplatin was assessed in patients with recurrent ovarian and primary peritoneal cancers. Methods: A two cohort phase 2 trial of cisplatin (60 mg/m2 IV) followed by flavopiridol (100 mg/m2 IV, 24 h continuous infusion; 21 day cycles) was undertaken in patients with recurrent platin-sensitive or platin-resistant ovarian/primary peritoneal cancers (defined by disease progression &gt; vs. &lt;6 months following platin-based therapy). Measurable disease (RECIST criteria) – or evaluable disease plus CA125 &gt;2X the post-treatment nadir – was required, as was ECOG performance &lt;2 and exposure to only one prior treatment regimen. Results: Forty-five patients were enrolled between April 20, 2004 and March 4, 2010 – 40 platin-resistant patients (Group 1), and 5 platin-sensitive patients (Group 2). In Group 1, the median number of treatment cycles was 3 (range 2-12); 39 of the 40 eligible patients have now discontinued treatment. While only 10% of all patients incurred grade 4 toxicities, grade 3 toxicities were seen in the majority (65%). The most frequent grade 3 and 4 toxicities were neutropenia (all grade 3, 17.5%); nausea (12.5%); vomiting, fatigue, thrombosis, anemia (10% each). Sensory neuropathy, grade 1 or 2, was observed in 75% of all patients – with grade 3 and 4 neuropathy not observed primarily due to pre-specified aggressive dose reductions. Six patients (15%) in Group 1 achieved a confirmed response (1 CR, 5 PR), with a median response duration of 119 days (range 84-212). Ten additional Group 1 patients (32.5%) experienced maintained stable disease. Median Group 1 overall time to progression was 3.7 months; overall survival was 17.2 months. Pilot assessment of attained ascites flavopiridol level and sensitivity of patient ascitic tumor cells to flavopiridol confirmed that patient flavopiridol levels were consistent with observed clinical antitumor efficacy. In Group 2, although 2 of 5 patients also responded (40%; 2 PR), the cohort was closed due to poor accrual. Conclusions: The combination of flavopiridol and cisplatin has promising clinical activity in both platin-sensitive and platin-resistant ovarian and primary peritoneal cancers. Supported in part by NCI CA097129, CA15083 and CM62205; clinicaltrials.gov identifier NCT00083122 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4712. doi:10.1158/1538-7445.AM2011-4712