BID Dose Level Research Articles

Abstract CT014: A large phase I study of TAS-114 in combination with S-1 in patients with advanced solid tumors

Abstract Background: Deoxyuridine triphosphatase (dUTPase) is the key gatekeeper enzyme that inhibits 5-fluorouracil (5-FU) misincorporation into DNA in tumor cells, and its overexpression is associated with resistance to 5-FU-based chemotherapy.1 TAS-114 is an oral dUTPase inhibitor and has shown favorable safety and preliminary efficacy in combination with S-1 in patients (pts) with advanced solid tumors.2 This Phase I study further evaluated TAS-114/S-1 combination therapy in advanced solid tumors (NCT02454062). Methods: Pts (≥18 years) with histologically or cytologically confirmed advanced solid tumors, ECOG performance status of 0 or 1, and who failed all standard therapies were enrolled. Primary objectives were safety and the maximum tolerated dose (MTD) of TAS-114 combined with S-1. Secondary objectives were pharmacokinetics (PK) and antitumor activity. In the dose-escalation phase, pts received an increasing dose of twice-daily (BID) TAS-114 (5 mg/m2 [dose level 1] to 240 mg/m2 [level 12]) + BID S-1 25 mg/m2 (levels 1-4), 30 mg/m2 (levels 5-11), or 36 mg/m2 (level 12) for 14 days with 7 days' rest in a 21-day cycle; the expansion cohort received the MTD. PK analyses were performed on day 1 (cycle 1) in both phases and following a single dose of S-1, 7-10 days before day 1 of treatment with TAS-114/S-1, in the expansion phase. Results: 99 pts were enrolled: 53.5% were male, median age was 59.4 years (36-78), and 81.8% were Caucasian. Most common cancer types were colorectal (n=43; 43.4%) and pancreatic (n=16; 16.2%), and 45 pts (45.5%) had ≥4 prior lines of anticancer therapy. In the dose-escalation phase (n=37), 3 pts had dose-limiting toxicities (1 in dose level 7 and 2 in level 12) and the MTD was determined to be TAS-114 240 mg/m2 + S-1 30 mg/m2 BID (dose level 11). PK analysis did not show any significant correlation between the plasma concentrations of TAS-114 and S-1 or its metabolites. In the expansion phase (n=62), grade ≥3 treatment-emergent adverse events (TEAEs) were reported in 47 pts (75.8%) and treatment related in 38 (61.3%). Overall, the most common grade ≥3 TEAEs were anemia (17.2%), rash (10.1%), asthenia (8.1%), neutropenia, and increased blood bilirubin (each 5.1%). Ten pts died during the study (none treatment related). PK interaction analysis in the expansion phase indicated similar exposure of 5-FU with S-1 alone and with TAS-114. Five pts had a partial response (1 each with breast, colorectal, and pancreatic cancer; 2 with non-small-cell lung cancer), 51 (51.5%) had stable disease (30 [68.4%] in the expansion cohort), and the objective response rate was 5.1% (8.1% in the expansion cohort). Conclusions: TAS-114 combined with S-1 demonstrated an acceptable safety profile and preliminary efficacy in heavily pretreated pts with advanced solid tumors. 1. Ladner RD et al. Cancer Res 2000; 60: 3493-3503. 2. Aoyama T et al. Eur J Cancer 2016; 69: S117-S118. Citation Format: Angelica Fasolo, Takekazu Aoyama, Anastasios Stathis, Christiana Sessa, Antoine Hollebecque, Jean Charles Soria, Alberto Sobrero, Jean-Luc Van Laethem, Kunihiro Yoshisue, Lucca Gianni. A large phase I study of TAS-114 in combination with S-1 in patients with advanced solid tumors [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 CT014.

Abstract CT012: Phase I study of TAS-114 in combination with capecitabine in patients with advanced solid tumors

Abstract Background: TAS-114 is a novel dual inhibitor of deoxyuridine triphosphatase and dihydropyrimidine dehydrogenase, and has shown favorable safety and preliminary efficacy in combination with S-1 or capecitabine in patients (pts) with advanced solid tumors.1,2 This Phase I study further evaluated the TAS-114/capecitabine combination in pts with advanced solid tumors (NCT02025803). Methods: Pts (≥18 years) with histologically or cytologically confirmed advanced solid tumors treated with standard anticancer therapy and an ECOG performance status of 0 or 1 were enrolled. Primary objective was safety and maximum tolerated dose (MTD) of TAS-114 combined with capecitabine; secondary objectives were pharmacokinetics (PK) and antitumor activity. In the dose-escalation phase, pts received an increasing dose of TAS-114 twice daily (BID; 10 mg/m2 [dose level 1] to 360 mg/m2 [level 12]) + capecitabine 380 mg/m2 BID (levels 1 to 9, 11, and 12) or capecitabine 450 mg/m2 BID (TAS-114, 240 mg/m2) for 14 days followed by 7 days' rest (21-day treatment cycle); the expansion cohort received the MTD. PK analyses were performed on days 1 and 14 of cycle 1 in the dose-escalation phase. Results: Of 104 pts, 68 (65.4%) were female, median age was 57 years (28-81), 49 (47.2%) were in the dose-escalation phase, and 55 (52.9%) were in the 2 expansion cohorts (mini [n=8] and MTD [n=47]). In the dose-escalation phase, the majority of pts had colorectal cancer (CRC; n=17; 16.3%) and breast cancer (BC; n=23; 22.1%). Dose-limiting toxicities were reported in 5 pts (1 each had grade 2 and 3 Palmar-plantar erythrodysesthesia, 2 had grade 2 rash, and 1 had grade 3 maculopapular rash). MTD was determined to be TAS-114 360 mg/m2 BID + capecitabine 380 mg/m2 BID (dose level 12). PK analysis on day 1 showed a significant correlation between TAS-114 dose and the Cmax (p=0.0013) and AUC0-last (p<0.0001) of 5-fluorouracil (5-FU), with an average maximum 5-FU AUC0-last of 712 ng·h/mL achieved at the MTD. Of 8 pts in the mini expansion cohort, 6 had CRC and 2 had BC; in the MTD expansion cohort, 29 had CRC and 18 had BC. Grade ≥3 treatment-emergent adverse events were reported in 39 pts (72.2%) and 67 (72.2%) in the overall population, with anemia (19.2%), fatigue (7.7%), stomatitis (6.7%), and maculopapular rash (5.8%) as the most common. No treatment-related deaths occurred during the study. In the 2 expansion cohorts, 2 pts (3.6%) had partial response (PR) and 18 (32.7%) had stable disease (SD) for ≥6 weeks. In the dose-escalation cohort, 3 pts (6.1%) had PR and 24 (48.9%) had SD. Conclusions: TAS-114 combined with capecitabine at 30% of its standard dose achieved an equivalently efficacious 5-FU exposure as the standard capecitabine dose alone, with acceptable safety and preliminary efficacy in pts with advanced solid tumors. 1. Aoyama T et al. Eur J Cancer 2016; 69: S117-8. 2. LoRusso P et al. Eur J Cancer 2016; 69: S119. Citation Format: Patricia M. LoRusso, Kathy D. Miller, Anthony F. Shields, Ki Y. Chung, Kunihiro Yoshisue, Takekazu Aoyama, Heinz-Josef Lenz. Phase I study of TAS-114 in combination with capecitabine in patients with advanced solid tumors [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 CT012.

Abstract CT050: A phase I dose escalation study of BGB-290 in Chinese subjects with advanced ovarian, fallopian, and primary peritoneal, or advanced triple-negative breast cancer

Abstract Background BGB-290 is a selective inhibitor of poly (ADP-ribose) polymerases (PARP) 1 and 2 that crosses the blood-brain barrier, showed potent DNA-PARP trapping, and demonstrated robust antitumor activity in nonclinical models. In a first-in-human study (NCT02361723), BGB-290 was generally well tolerated and showed promising preliminary antitumor activity, notably in patients (pts) with high-grade non-mucinous ovarian cancer (HGOC). The recommended Phase 2 dose (RP2D) was established as 60 mg PO BID. Methods This ongoing dose-escalation (DE)/expansion study (NCT03333915) is enrolling Chinese pts with advanced HGOC, including fallopian and primary peritoneal cancer, or triple-negative breast cancer (TNBC). DE cohorts were designed to confirm the previously established RP2D. Patients with germline BRCA1/2 mutation (BRCA+) were retrospectively identified by central testing. The primary endpoint was safety and tolerability of BGB-290 in Chinese patients as per CTCAE v4.03. Key secondary endpoints were pharmacokinetics (PK) and antitumor activity as per RECIST v1.1. Results As of 25 Sep 2017, 15 pts (HGOC: n=9; TNBC: n=6) were enrolled in DE. Median age was 49 years (range: 32–70), ECOG score was 0 (n=2) or 1 (n=13), and 7 of 15 pts were germline BRCA+ (HGOC: n=5; TNBC: n=2). BGB-290 BID dose levels of 20 mg (n=4), 40 mg (n=4), and 60 mg (n=7) were evaluated. Most common treatment-related adverse events (AEs) were asthenia (n=12), nausea (n=12), decreased appetite (n=9), decreased white blood cell (WBC) count (n=9), anemia (n= 8), and decreased neutrophil count (n=7). Grade 3 AEs occurring in ≥2 pts were anemia (n=5), decreased neutrophil count, and decreased WBC (n=2 each). No ≥ Grade 4 AEs were reported. Serious AEs (abdominal infection, ileus, and pleural effusion, n=1 each) were determined not related to BGB-290. No dose-limiting toxicities were reported, and the RP2D was confirmed as 60 mg PO BID. After a single dose, BGB-290 was rapidly absorbed (median Tmax=1 hr) with a t1/2 of ~12 hr and showed near dose-proportional increases for both Cmax and AUC0-inf. Preliminary activity showed 2 confirmed PRs (BRCA+=1) and 6 SD (BRCA+=4) in HGOC pts (all platinum-resistant/refractory); median duration of treatment is 133 days (range: 8–260) with 5 pts still on treatment. Best response in the 5 TNBC pts was PD (BRCA+=1). Conclusions BGB-290 at 20, 40, and 60 mg PO BID was generally well tolerated in Chinese pts with advanced HGOC or TNBC. The previously established RP2D of 60 mg BID was confirmed. Preliminary antitumor activity in HGOC pts previously resistant or refractory to platinum is consistent with other reports. Enrollment in the expansion stage is ongoing. Citation Format: Binghe Xu, Yongmei Yin, Yan Song, Wei Li, Xiang Huang, Rainer Brachmann, Tristin Tang, Haiyuan Yang, Ruimin Ge, Song Mu, Kathy Zhang, Miao Li, Mei Dong. A phase I dose escalation study of BGB-290 in Chinese subjects with advanced ovarian, fallopian, and primary peritoneal, or advanced triple-negative breast cancer [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 CT050.

Abstract LB-039: Translational research in a phase I proof-of-concept study supports that DCC-2618 is a pan-KIT inhibitor

Abstract Background: DCC-2618 is a potent switch control inhibitor of KIT and PDGFRα kinases maintains potent inhibition of mutant forms across all exon regions in preclinical models. Gastrointestinal stromal tumor (GIST) is an important disease to achieve a proof-of-concept due to the heterogeneity of resistance mutations in KIT which emerge on treatment with approved KIT inhibitors. In later lines of therapy resistance mechanisms independent of the KIT gene have also been described. Methods: The ongoing phase 1, PK-guided dose escalation study of DCC-2618 given orally BID [28-day cycle] tested doses from 20 mg to 200 mg in patients (pts) with advanced solid tumors including GIST (NCT02571036). We report preliminary longitudinal results of plasma cell free (cf) DNA sequencing by Guardant 360 collected throughout the study and levels of circulating tumor cells (CTCs) based on a viral telomerase promoter-driven GFP expression assay. Results: To date, 24 out of 31 enrolled pts had metastatic KITm GIST refractory to standard therapy. A high, total mean exposure of DCC-2618 and its active metabolite was achieved at 100 and 150 mg BID, affording steady state Cmax >5 µM in Cycle 1. Starting with 50 mg BID dose level, concentrations of total drug exceeding IC90 of the most resistant mutations to DCC-2618 were achieved. Next-generation sequencing of plasma cfDNA revealed a total of 40 KIT mutations in 16 of 18 GIST pts at baseline. DCC-2618 led to rapid decrease and/or clearance of the heterogeneous array of KIT mutations from plasma cfDNA including exons 9, 11, 13, 14, 17, and 18. Independent of suppressed KIT mutation burden, longitudinal monitoring of cfDNA revealed changes in non-KIT oncogenic mutations which may contribute to heterogenous mechanisms of resistance. KIT mutation burden will be correlated with metabolic response assessment by PET scans and exposure to DCC-2618. CTCs have been detected in blood from all GIST patients at baseline using a non-biased assay capable of identifying sarcoma cells. Preliminary result show that CTCs with immunofluorescent detection of KIT or PDGFRα, corresponding to their respective mutational status, show 1 of 3 patterns when compared to radiologic response: most pts show relatively stable low levels at stable disease (SD), a minority of pts with prolonged SD a decline in CTCs and 2 pts with progressive disease had significant increase in KIT positive CTCs. Conclusions: DCC-2618 and its active metabolite achieved high plasma concentrations sufficient to inhibit the most resistant KIT mutations at well-tolerated exposures. Monitoring of cfDNA KIT mutation frequency demonstrates rapid clearance of a broad spectrum of KIT mutations in this heavily pretreated GIST patient population and suggests candidate resistance genes that are independent of KIT. Our data provide a first signal that CTC monitoring might represent a potential marker for tumor control in KIT mutant GIST. Citation Format: Filip Janku, Albi Razak, Michael Gordon, David Brooks, Daniel Flynn, Anu Gupta, Michael Kaufman, Cynthia Leary, Bryan Smith, Deb Westwood, Neeta Somaiah, Elena Helman, Eric Gerstenberger, Oliver Rosen, Suzanne George. Translational research in a phase I proof-of-concept study supports that DCC-2618 is a pan-KIT inhibitor [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 LB-039. doi:10.1158/1538-7445.AM2017-LB-039

Pharmacokinetic-driven phase I study of DCC-2618 a pan-KIT and PDGFR inhibitor in patients (pts) with gastrointestinal stromal tumor (GIST) and other solid tumors.

2515 Background: DCC-2618 is a potent switch control inhibitor of KIT and PDGFR kinases active in a broad range of mutations. GIST is an important disease to achieve a proof-of-concept due to the heterogeneity of KIT resistance mutations, which emerge on treatment with approved KIT inhibitors. Methods: This was a PK-guided dose escalation study of oral DCC-2618 (QD or BID q28 days) in advanced solid tumors. FDG-PET scans were used to assess changes in FDG uptake in GIST pts after 3 wks of therapy. Next generation sequencing (NGS) of plasma cell-free (cf) DNA was performed throughout the study to assess and quantify KIT and other molecular alterations in drug targets and potential mechanisms of resistance. Results: 38 pts were enrolled (30 GIST; 4 glioma; 1 mastocytosis, 3 other carcinoma) to 8 dose levels: BID doses: 20 (4 pts), 30 (4), 50 (5), 100 (6), 150 (6) and 200 mg (3); QD doses: 100 (5) and 150 mg (4). Safety of evaluable pts is as follows: G3 or G4 adverse effects (regardless of attribution and occurring in > 1 pt) included anemia (5), lipase increase (4), hypertension (2). Two of the G3/4 lipase increase at 100 mg BID and 200 mg BID were DLTs. All G3/4 lipase increase were asymptomatic. G1/2 AEs (considered at least possibly related to DCC-2618) and occurring in ≥15% (n > 5) of pts include fatigue (12), alopecia & lipase increase (7), weight decrease (6). Starting with 50 mg BID dose level, trough concentrations of total drug exceeded the IC90 of the least sentivitive KIT mutations. Plasma concentrations > 5μM were achieved starting at 100 mg BID and the selection of the expansion phase dose is being finalized. Of 18 pts with KIT mutant GIST assessed by FDG PET, 14 (78%) had partial metabolic response per EORTC criteria. RANO/RECIST partial responses (PRs) were reported in 3 patients (1 GBM with PDGFRA/KIT amplifications and 2 GIST with Ex 11 & 17 / Ex 11 & 18 mutations, respectively). NGS of plasma cfDNA revealed 44 KIT mutations in baseline samples from 19 of 21 pts with GIST. Conclusions: DCC-2618 is well tolerated with encouraging preliminary activity in GIST pts with a broad spectrum of mutations and prior therapies. PR was also seen in a pt with GBM with PDGFRA/KIT amplifications. Clinical trial information: NCT02571036.

A multicenter phase II study of donafenib in patients with advanced hepatocellular carcinoma.

e15682 Background: In an early dose-escalation study, Donafenib, a new oral multikinase inhibitor, showed antitumor activity and favorable tolerability in treatment of different type solid tumors including HCC at both 0.2g bid and 0.3g bid dose levels. This prospective study aimed to evaluate the safety and efficacy of Donafenib in the patients with advanced HCC. Methods: In this phase 2 study, patients with unresectable HCC, who had Child-Pugh class A liver function and received no prior systemic therapy were enrolled across 10 sites in China. All patients received oral Donafenib 0.2g bid or 0.3g bid for several 4-week cycles, based on 1:1 randomization ratio. The radiology assessment was done every 8 weeks. The primary end points were safety and tolerability; secondary endpoints were time to progression assessed by an independent radiology committ, ORR , DCR, and PK. Results: Between June 17, 2014, and May 4, 2015, total 106 patients were enrolled and included in the safety analyses. Of them, 52 received donafenib 0.2g bid and 54 received 0.3g bid. The most common adverse events that led to dose discontinuation or reductions were hand-foot skin reaction in 10 (9.4%) patients (2 vs 8), liver dysfunction in 4 (3.8%) patients (1 vs 3), and leukopenia in 2 (1.9%) patients (1 vs 1). Other reported AEs caused dose reductions were hypertension, thrombocytopenia, throat ache, and cough. The median duration maintained for the initial dose was 90 and 72 days, respectively. The full analysis set for TTP includes104 patients (51and 53, respectively) and the per-protocol analysis set for ORR and DCR includes 84 patients (40 and 44, respectively). Median TTP was 111 days in 0.2g group compared with 110 days in 0.3g group (HR 0.99, 95% CI [0.62, 1.60]). At the Week 16, there were no complete responses in both groups, but partial response was confirmed in 4 (4.8%) patients (2 vs 2); and stable disease was in 35 (41.7%) patients (17 vs 18). Conclusions: Donafenib 0.2g bid and 0.3g bid were well tolerated. Significant adverse events were reported more frequently in 0.3g group. Both regimens showed similar treatment responses for patients with HCC, while 0.2g bid seems to be an appropriate first line therapeutic option for the treatment of HCC. Clinical trial information: NCT02229071.

BBI608-503-103HCC: A phase Ib/II clinical study of napabucasin (BBI608) in combination with sorafenib or amcasertib (BBI503) in combination with sorafenib (Sor) in adult patients with hepatocellular carcinoma (HCC).

4077 Background: Napabucasin, a first-in-class cancer stemness inhibitor in clinical development, suppresses cancer stemness by targeting STAT3-driven gene transcription. Amcasertib targets multiple serine threonine stemness kinases and inhibits Nanog and other cancer stemness pathways. Preclinically, potent and broad-spectrum anti-cancer activity was observed in vitro and in vivo, alone and in combination with sorafenib. Methods: A phase Ib/II open-label, multi-center study in adult patients with advanced HCC who have not received prior systemic chemotherapy was performed to determine the safety, tolerability, and recommended Phase II dose (RP2D) ,according to the criteria for DLT and for dose-escalation of Napabucasin (Arm 1), administered at 160 mg BID (dose level I) and at 240 mg BID (dose level II) in combination with sorafenib and of Amcasertib (Arm 2), administered at 100 mg QD (dose level I) and at 200 mg QD (dose level II) in combination with sorafenib. Results: 20 pts were enrolled, 10 in Arm 1 and 10 in Arm 2. 12 patients were evaluable for DLT determination; 2 pts d/c prior to starting protocol treatment; 11 pts received evaluation by RECIST, 6 pts in Arm 1 and 5 pts in Arm 2. The safety profile was consistent with that of each agent as monotherapy and most common AEs were attributed to (Sor) and included rash, PPE, grade 1/2 diarrhea, nausea, abdominal cramps, and vomiting. No signs of drug-drug interactions were observed in pharmacokinetics. Among all patients who received RECIST evaluation, Disease Control Rate (DCR=CR+PR+SD) for Arm 1 was 100% (6/6pts) and 100% (5/5pts) for Arm 2. DCR in ITT Arm 1 population was 67% and 50% in Arm 2. Median OS is not yet reached. Conclusions: In this phase Ib study, RP2D were determined for napabucasin and amcasertib to be safely combined with sorafenib at full dose, showing encouraging anti-tumor activity in patients with HCC who have not received prior systemic chemotherapy. A randomized phase II is schedule to start. Clinical trial information: NCD02279719. [Table: see text]

Phase I/II Study of Ruxolitinib (RUX) with Decitabine (DAC) in Patients with Post-Myeloproliferative Neoplasm Acute Myeloid Leukemia (post-MPN AML): Phase I Results

Phase I/II Study of Ruxolitinib (RUX) with Decitabine (DAC) in Patients with Post-Myeloproliferative Neoplasm Acute Myeloid Leukemia (post-MPN AML): Phase I Results

A phase I, pharmacokinetic and pharmacodynamic study of GSK2256098, a focal adhesion kinase inhibitor, in patients with advanced solid tumors

Focal adhesion kinase (FAK) is important in cancer growth, survival, invasion, and migration. The purpose of this study was to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the FAK inhibitor, GSK2256098, in cancer patients. The dose of GSK2256098 was escalated, in cohorts of patients with advanced cancer, from 80 to 1500 mg, oral twice daily (BID), until the MTD was determined. Serial blood samples were obtained from all patients, and the PK was determined. Paired tumor biopsies were obtained in select patients, and the level of phospho-FAK (pFAK) was determined. Sixty-two patients (39 males, 23 females; median age 61 y.o., range 21-84) received GSK2256098. Dose-limiting toxicities of grade 2 proteinuria (1000 mg BID), grade 2 fatigue, nausea, vomiting (1250 mg BID), and grade 3 asthenia and grade 2 fatigue (1500 mg BID) were reported with the MTD identified as 1000 mg BID. The most frequent adverse events (AEs) were nausea (76%), diarrhea (65%), vomiting (58%), and decreased appetite (47%) with the majority of AEs being grades 1-2. The PK was generally dose proportional with a geometric mean elimination half-life range of 4-9 h. At the 750, 1000, and 1500 mg BID dose levels evaluated, the pFAK, Y397 autophosphorylation site, was reduced by ∼80% from baseline. Minor responses were observed in a patient with melanoma (-26%) and three patients with mesothelioma (-13%, -15%, and -17%). In the 29 patients with recurrent mesothelioma, the median progression-free survival was 12 weeks with 95% CI 9.1, 23.4 weeks (23.4 weeks merlin negative, n = 14; 11.4 weeks merlin positive, n = 9; 10.9 weeks merlin status unknown, n = 6). GSK2256098 has an acceptable safety profile, has evidence of target engagement at doses at or below the MTD, and has clinical activity in patients with mesothelioma, particularly those with merlin loss.

Combination Trial of Duvelisib (IPI-145) with Bendamustine, Rituximab, or Bendamustine/Rituximab in Patients with Lymphoma or Chronic Lymphocytic Leukemia

Background: Duvelisib, a potent inhibitor of the δ and γ isoforms of phosphoinositide-3-kinase (PI3K) is being developed as a potential therapeutic in hematologic malignancies including chronic lymphocytic leukemia (CLL), as well as B and T cell lymphoma. Single agent bendamustine (B), rituximab (R), and their combination have demonstrated proven activity in iNHL and CLL. Combining duvelisib with bendamustine or rituximab alone or with both drugs may improve response rates and the durability of remission. The primary objective of this trial is to characterize the safety, maximum tolerated dose (MTD), and a preliminary efficacy profile of duvelisib given in combination with rituximab (Arm 1-DR), bendamustine plus rituximab (Arm 2-DBR) or bendamustine (Arm 3-DB) in subjects with select relapsed/refractory lymphoma or CLL.Methods: Pts with relapsed CLL or NHL, ECOG performance status (PS) ≤2, and adequate organ function were enrolled. The subject population during dose escalation was limited to relapsed NHL. During the dose expansion phase, each treatment arm enrolled to population specific cohorts to continue to assess efficacy. Arm 1 (DR) received rituximab 375 mg/m2 IV weekly for 2, 28 day cycles plus duvelisib PO BID until disease progression or intolerance. Arm 2 (DBR)received rituximab 375 mg/m2 IV weekly for 2, 28 day cycles, bendamustine 90 mg/m2 IV for NHL pts or 70 mg/m2 IV for CLL pts on Days 1 and 2 of the first six cycles plus duvelisib PO BID until disease progression or intolerance. Arm 3 (DB) received bendamustine 120 mg/m2 IV on Days 1 and 2 of the first six cycles plus duvelisib PO BID up to 12 cycles. Three different dose levels of duvelisib, 25, 50, and 75 mg PO BID were initially explored. Pts were evaluated for response every 3 cycles according to specific criteria for their disease.Results: Between August 2013 and April 2015, 48 pts, median age 67 yrs (40-83) were enrolled; 12 NHL pts in the dose escalation portion and 36 pts (18 CLL, 18 NHL) in dose expansion. Pts had a median of 2 prior therapies (1-7). In arms 1 (DR) and 2 (DBR), no dose limiting toxicities were seen at the highest dose level of duvelisib (75 mg bid). In arm 3 (DB), with a higher dose of bendamustine, 1 pt developed a DLT at the 50 mg BID dose level of duvelisib (febrile neutropenia, neutropenia ≥ 7 days, thrombocytopenia ≥ 7 days, and liver toxicities which resulted in a treatment delay of ≥ 7 days). The MTD was not reached in this study but given recent data of single agent duvelisib showing no advantage in doses >25 mg BID, pts on the expansion phase were treated with 25mg BID. The AE profile of the drug combination is consistent with toxicities of the single agents (Table 1). There have been 2 potentially treatment-related deaths (cardiac arrest in a pt with history of hypertension and diabetes, and pneumonia), both on Arm 1. 38 pts were evaluable for response with an ORR of 74% (8% CR, 66% PR, 16% SD and 10% PD). The ORR of NHL and CLL pts were 64% and 92% respectively. With a median follow up of 16.25 mos, median progression free survival is 13.7 mos overall. Median overall survival (OS) has not been reached, but 15 mo OS probability is 82%. Pharmacokinetics analysis is consistent with the monotherapy Phase I trial of duvelisib (Figure 2) and is not effected by bendamustine.Conclusions: Analysis of duvelisib administered in combination with bendamustine and rituximab shows these combinations to be generally well-tolerated with encouraging response. Further follow-up is required to better characterize both response rates and durability of remissions.Table 1Treatment-related AEs (≥15% all pts)ARM 1 (N=28)ARM 2 (N=18)ARM 3 (N=2)Preferred TermG 1/2G 3/4G 1/2G 3/4G 1/2G 3/4Treated (N=48)RASH8 (29%)3 (11%)3 (17%)3 (17%)017 (35%)DIARRHEA8 (29%)3 (11%)2 (11%)1 (6%)1 (50%)015 (31%)FATIGUE9 32%)04 (22%)1 (6%)1 (50%)015 (31%)NAUSEA5 (18%)04 (22%)01 (50%)010 (21%)ALANINE AMINOTRANSFERASE INCREASED5 (18%)1 (4%)3 (17%)0009 (19%)NEUTROPENIA1 (4%)5 (18%)03 (17%)009 (19%)ASPARTATE AMINOTRANSFERASE INCREASED4 (14%)1 (4%)3 (17%)0008 (17%)ANAEMIA3 (11%)1 (4%)2 (11%)01 (50%)07 (15%)PRURITUS3 (11%)03 (17%)0006 (13%)UPPER RESPIRATORY TRACT INFECTION5 (18%)01 (6%)0006 (13%)CONSTIPATION4 (14%)01 (6%)0005 (10%)MUCOSAL INFLAMMATION3 (11%)1 (4%)1 (6%)0005 (10%) [Display omitted] DisclosuresFlinn:Celgene Corporation: Research Funding. Berdeja:Curis: Research Funding; Abbvie: Research Funding; Janssen: Research Funding; Array: Research Funding; Acetylon: Research Funding; Takeda: Research Funding; Celgene: Research Funding; BMS: Research Funding; Onyx: Research Funding; MEI: Research Funding; Novartis: Research Funding.

O7.3 - BET-bromodomain (BRD) inhibitor OTX015: Final results of the dose-finding part of a phase I study in hematologic malignancies

ABSTRACT Background: OTX015 (Oncoethix) is a small molecule that specifically binds to BRDs 2, 3 and 4, thereby inhibiting binding to acetylated histones, resulting in downregulation of several oncogenes driven by super-enhancers. The therapeutic potential of BRD inhibitors has been demonstrated in several preclinical models including hematologic malignancies. Methods: The primary end point of this dose escalation study (3 + 3 design) was to establish the Phase 2 recommended dose (P2RD) and schedule in two independent cohorts of patients (pts) with either relapsed/refractory acute leukemia (AL) or other hematologic malignancies (OHM). OTX015 was given orally, daily (qd), with 1 bidaily (bid) dose level (DL) explored, continuously in OHM or for 14 days ON/7 days OFF in AL. Results: From January 2013 to August 2014, 41 pts with AL (AML 37; ALL 3) or high-risk myelodysplastic syndrome (HR-MDS 1) and 45 pts with OHM (22 diffuse large B-cell lymphoma [DLBCL], 11 other lymphomas, 12 multiple myeloma) were enrolled over 7 DLs from 10 to 160 mg. Dose-limiting toxicities (DLT) during the first treatment cycle were observed at doses >120 mg in AL (diarrhea, asthenia) and doses >80 mg in OHM (primarily thrombocytopenia). Additionally, both AL and OHM pts treated at >80 mg experienced grade 1-2 gastrointestinal events (diarrhea, dysgueusia) that hampered compliance, though not meeting DLT criteria. PK showed dose-proportional OTX015 exposure (AUC0-24h) up to 120 mg qd; trough plasma concentrations at 80 mg qd reached the GI50 cut-off of 500 nM for sensitive tumor cell lines in vitro. Two complete remissions (CR) and 1 CR with incomplete recovery (CRi) were observed in pts with relapsed/refractory HR-MDS or AML secondary to MDS and 2 CR and 1 partial response in DLBCL pts. OTX015 P2RD was determined as 80 mg qd with a 14 days ON/7days OFF schedule, based on kinetics of platelet nadir and recovery. Conclusion: OTX015 is an orally available molecule showing dose-proportional exposure up to 120 mg qd with a favorable tolerance profile, and evidence of clinical activity in refractory DLBCL and AML/HR-MDS. Expansion cohorts in AML secondary to MDS, de novo AML and DLBCL at the P2RD are ongoing.

Preoperative infusional 5-FU and sorafenib with external radiation therapy in locally advanced rectal cancer: Results of a phase I study.

683 Background: The standard of care in locally advanced rectal cancer (T3, T4, or N1) is preoperative treatment with fluoropyrimidine-based chemotherapy. Sorafenib works synergistically with radiation (RT), and inhibits ras/raf, PDFGR and VEGFR. This phase I study evaluated the safety and efficacy of sorafenib with infusional 5-FU and RT in patients with locally advanced rectal cancer. Methods: Patients with confirmed stage II or III rectal cancer were recruited in 4 cohorts of 3 patients per dose level (DL), with an expansion cohort at the MTD. A 3+3 dose escalation design was used. RT was given in 25 fractions at 1.8Gy (45 Gy) day 1-5 at all dose levels. 6-10 weeks following neoadjuvant therapy, patients underwent surgery. Results: 17 patients were enrolled at Moffitt Cancer Center, including 10 females and 7 maleswith a median age of 54years (range: 31-72).After observing toxicity in the first cohort (2 patients with G2 and G3 skin toxicity and 1 patient with G2 mucositis) requiring dose interruptions, an amendment was made to change the schedule of chemotherapy and sorafenib to days 1-5 instead of daily.Following this, the primary G3 toxicity was hypertension, in 2 patients at 200 mg adjusted DL (day 1-5) and 1 patient at the 400 mg PO BID DL. 1 patient had G3 ALT elevation at the 400 mg PO BID DL, and no grade IV toxicities were observed. G1 and G2 toxicities included diarrhea, mucositis, nausea, fatigue, proctitis, and thrombocytopenia. No perioperative complications were seen. One patient is awaiting surgery. Due to patient refusal, 2 patients did not undergo surgery.The pCR rate was 35.7% and downstaging was observed in 85.7% of patients.KRAS status was available for 12 patients. The pCR was 40% in those with KRASmutant tumors (2/5 pts). Median NAR (neoadjuvant rectal cancer) score was 8.4. Conclusions: This regimen was very well tolerated after changing the dosing schedule. The pCR and downstaging rate is encouraging, and supports further clinical investigation of this regimen. Clinical trial information: NCT01376453. [Table: see text]

An Open-Label, Phase Ib Study of Duvelisib (IPI-145) in Combination with Bendamustine, Rituximab or Bendamustine/Rituximab in Select Subjects with Lymphoma or Chronic Lymphocytic Leukemia

Background: Duvelisib is a potent inhibitor of the δ and γ isoforms of phosphoinositide-3-kinase (PI3K) being developed as a potential therapeutic in hematologic malignancies including B and T cell lymphoma and chronic lymphocytic leukemia (CLL). In a phase I study of single agent duvelisib (D), ORR of 52% was seen in pts with indolent non-Hodgkin’s lymphoma (iNHL) and 47% in CLL. Bendamustine (B), rituximab (R), and their combination have demonstrated proven activity in iNHL and CLL. Combining duvelisib with either bendamustine or rituximab alone or in combination with each other may improve response rates and the durability of remission. The goal of this Phase 1b, open-label, three-arm, non-randomized, dose escalating, safety and tolerability trial is to characterize the safety, maximum tolerated dose (MTD) and preliminary efficacy profile of duvelisib given in combination with rituximab (Arm 1-DR), bendamustine plus rituximab (Arm 2-DBR) or bendamustine (Arm 3-DB) in subjects with select relapsed/refractory lymphoma or CLL.Methods: Pts had relapsed CLL or NHL, ECOG performance status (PS) ≤2, and adequate organ function. The subject population during dose escalation was limited to relapsed NHL. During the dose expansion phase, each treatment arm enrolled to population specific cohorts to continue to assess efficacy. Arm 1 (DR) received rituximab 375 mg/m2 IV weekly for 2, 28 day cycles plus duvelisib PO BID up to 12 cycles. Arm 2 (DBR)received rituximab 375 mg/m2 IV weekly for 2, 28 day cycles, bendamustine 90 mg/m2 IV on Days 1 and 2 of the first six cycles plus duvelisib PO BID up to 12 cycles. Arm 3 (DB) received bendamustine 120 mg/m2 IV on Days 1 and 2 of the first six cycles plus duvelisib PO BID up to 12 cycles. Three different dose levels of duvelisib were explored, 25, 50, and 75 mg PO BID. DLTs were defined as: febrile neutropenia, G4 neutropenia ≥7 days, G4 thrombocytopenia ≥ 7 days or G3 thrombocytopenia with bleeding, Grade 4 AST/ALT, Grade 2 hyperbilirubinemia ≥7 days, ≥ Grade 3 non-hematologic toxicity ≥7 days (excluding alopecia), Treatment delay of ≥7 days due to unresolved toxicity that prevents re-dosing, hepatocellular injury (defined as ALT>2 x ULN and (ALT/ULN)/(ALP/ULN) >5) and bilirubin >2 x ULN or jaundice ± alkaline phosphatase <2 x ULN. Patients were evaluated for response every 3 cycles according to specific criteria for their disease.Results: Between August 2013 and May 2014, 32 pts, median age 66 years (44-78) were enrolled to the study, 12 NHL pts on the dose escalation portion and 20 pts on dose expansion (13 CLL, 7 NHL). Patients had a median of 4 prior therapies (1-11). In arms 1 (DR) and 2 (DBR), no dose limiting toxicities were seen at the highest dose level of duvelisib (75 mg bid). In arm 3 (DB) in which a higher dose of bendamustine is used 1 pt developed a DLT at the 50 mg BID dose level of duvelisib (febrile neutropenia, neutropenia ≥ 7 days, thrombocytopenia ≥ 7 days, and liver toxicities which resulted in a treatment delay of ≥ 7 days). Dose escalation continues in this arm as the MTD has not reached. Patients on the dose expansion portion of the study are receiving duvelisib at 25 mg BID due to emerging data of duvelisib monotherapy showing no advantage in doses greater than 25 mg BID in these histologies. The AE profile is consistent with the toxicities of the single agents. The most common AEs > grade 3 were neutropenia (28% overall; [Arm 1 (DR), 27%]; [Arm 2 (DBR), 38%]), and rash (16% overall; [Arm 1, 14%]; [Arm 2, 25%]). Grade 3 or higher AST/ALT increases were seen in 2 out of 12 patients on Arm 1, 2 out of 8 patients on Arm 2 and no patients on Arm 3. There have been 2 deaths (cardiac arrest and pneumonia), both on Arm 1. Twenty one pts were evaluable for response with an ORR of 81% (10% CR, 71% PR, 14% SD and 5% PD). With a median follow up of 4.0 months, time to event analyses are immature. However, Kaplan-Meier estimate of PFS at 3 months is 87%. PK analysis is consistent with the monotherapy Phase I trial of duvelisib.Conclusions: Initial early analysis of duvelisib administered in combination with bendamustine and rituximab suggests these combinations to be generally well-tolerated with encouraging. Further follow-up is required to better characterize response rates and durability of remissions. DisclosuresFlinn:Infinity Pharmaceuticals: Research Funding. Matous:Infinity Pharmaceuticals: Research Funding.

Abstract CT407: Phase I study of preoperative continuous 5-fu and sorafenib with external radiation therapy in locally advanced rectal adenocarcinoma

Abstract Background: Preoperative treatment with fluoropyrimidine-based chemoradiotherapy is considered standard therapy for locally advanced rectal cancer( T3, T4 or N1). Sorafenib is an inhibitor of ras/raf, PDFGR and VEGFR with synergistic activity with radiation. The phase I trial evaluated the safety and efficacy of sorafenib in combination with infusional 5-FU and radiation Methods: Patients with stage II or III patients confirmed by EUS and CT scan were recruited in cohorts of 3 patients per dose level (DL). A 3+3 dose escalation design was used. On all dose levels RT was given in 25 fractions at 1.8Gy (45Gy) day 1- 5. Surgery was done 6-10 weeks after the completion of neoadjuvant treatment. Results: At Moffitt Cancer we enrolled 12 patients in 4 cohorts. 8 females(67%) and 4 males(33%); Median age is 55(range: 40-72). After observing toxicity in first cohort ( 2 pts with with G2 and G3 skin toxicity and 1 pt with G2 mucositis) which required dose interruptions, amendment was made to change the schedule of chemotherapy and sorafenib to days 1-5 instead of daily. After the amendment, hypertension was the only grade III toxicity observed. 2 patients had G3 hypertension at 200mg adjusted dose(day1-5); 1 patient had G3 hypertension at 400 mg PO BID dose level and no grade IV toxicities were seen. No perioperative complications related to the study drugs were seen. 2 patients never went to surgery due to patient refusal. KRAS testing information was available on 10 patients. pCR rate was 30 % and downstaging was observed in 80% of the patients. pCR was 50% in patients with Kras mutant tumors ( 2/4 pts) Conclusion: After changing the schedule of the chemotherapy, the regimen was very well tolerated. pCR and downstaging rate of the tumor seems to be encouraging. Plan is to open up an expansion cohort at DL3 to gather more safety and efficacy data. Schedule of sorafenib dose escalationDose level ( 3 patients each)Sorafenib5-FU infusion Rate (mg/m2/24hrsDL 1 before amendment200mg PO QD225 on day 1-7 for 5½ weeksDL 1 after amendment200mg PO QD( Day1-5)225 on day 1-5 for 5½ weeksDL 2 after amendment400mg PO QD( Day1-5)225 on day 1-5 for 5½ weeksDL 3 after amendment400mg PO BID( Day1-5)225 on day 1-5 for 5½ weeks Citation Format: Richard Kim, Kun Jiang, Xiuhua Zhao, Dung-Tsa Chen, Tiffany Campos, Sara Hoffe, Ravi Shridhar, David Shibata. Phase I study of preoperative continuous 5-fu and sorafenib with external radiation therapy in locally advanced rectal adenocarcinoma. [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 CT407. doi:10.1158/1538-7445.AM2014-CT407

Sorafenib use in hepatocellular carcinoma: More questions than answers

Sorafenib use in hepatocellular carcinoma: More questions than answers

Preclinical Drug Metabolism and Pharmacokinetics, and Prediction of Human Pharmacokinetics and Efficacious Dose of the Investigational Aurora A Kinase Inhibitor Alisertib (MLN8237)

Alisertib (MLN8237) is an investigational potent Aurora A kinase inhibitor currently under clinical trials for hematological and nonhematological malignancies. Nonclinical investigation showed that alisertib is a highly permeable compound with high plasma protein binding, low plasma clearance, and moderate volume of distribution in rats, dogs, monkeys and chimpanzees. Consistent with the above properties, the oral bioavailability in animals was greater than 82%. The predicted human oral pharmacokinetic (PK) profile was constructed using allometric scaling of plasma clearance and volume of distribution in the terminal phase from animals. The chimpanzee PK profiles were extremely useful to model absorption rate constant, which was assumed to be similar to that in humans, based on the fact that chimpanzees are phylogenetically closest to humans. The human plasma clearance was projected to be low of 0.12 L/hr/kg, with half-life of approximately 10 hr. For human efficacious dose estimation, the tumor growth inhibition as a measure of efficacy (E) was assessed in HCT116 xenograft mice at several oral QD or BID dose levels. Additionally, subcutaneous mini-pump infusion studies were conducted to assess mitotic index in tumor samples as a pharmacodynamic (PD) marker. PK/PD/E modeling showed that for optimal efficacy and PD in the xenograft mice maintaining a plasma concentration exceeding 1 µM for at least 8-12 hr would be required. These values in conjunction with the projected human PK profile estimated the optimal oral dose of approximately 103 mg QD or 62.4 mg BID in humans. Notably, the recommended Phase 2 dose being pursued in the clinic is close to the projected BID dose.

Target Engagement, Pathway Inhibition, and Efficacy Of The Bruton's Tyrosine Kinase (Btk) Inhibitor CC-292

Target Engagement, Pathway Inhibition, and Efficacy Of The Bruton's Tyrosine Kinase (Btk) Inhibitor CC-292

Phase 1 Study Of Single Agent CC-292, a Highly Selective Bruton's Tyrosine Kinase (BTK) Inhibitor, In Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

IntroductionCC-292, an oral, highly selective, small-molecule irreversible-inhibitor of Btk is under investigation for the treatment of CLL and other B-cell malignancies. This phase 1 trial investigated the safety, dose limiting toxicities (DLT), and clinical activity of CC-292 monotherapy in subjects with relapsed or refractory (R/R) CLL or non-Hodgkin's lymphoma. This interim analysis focused on the safety and clinical activity in subjects with CLL and small cell lymphocytic leukemia (SLL). MethodsEligible subjects with R/R (≥ 1 prior therapy) CLL/SLL were treated with monotherapy CC-292 in a dose-escalation study with doses ranging from 125 mg to 1000 mg QD and BID dose levels of 375 mg and 500 mg. As a maximum tolerated dose was not established, CLL patients have been enrolled in an early dose expansion cohort of 750 mg QD and preliminary recommended phase 2 dose expansion cohort at 500 mg BID. All subjects received continuous dosing in 28-day cycles until progressive disease or intolerable toxicity. Clinical activity was investigator assessed per the 2008 iwCLL criteria. Results83 subjects with R/R CLL/SLL have been enrolled as of June 30, 2013. Baseline characteristics include median age of 67 years (34-89), 52% Rai stage 3/4 disease, median 3 prior therapies (1-12), and 34% refractory to last treatment. Poor-risk factors were present in 67% of subjects, including del11q (22%), del17p (24%), and unmutated IgVH (54%). 67% of subjects remain on study. Subjects have received a median of 6 treatment cycles (0.2-21.6).The most frequent grade 3/4 adverse events (AEs) included neutropenia (21%), thrombocytopenia (15%), pneumonia (10%), and anemia (8%). Rates of febrile neutropenia were low (4%). The most common treatment-emergent AEs (≥ 10% of subjects) were diarrhea (59.7%), fatigue (37.5%), neutropenia (26.4%), thrombocytopenia (26.4%), nausea (26.4%), pyrexia (22.2%), headache (19.4%), cough (19.4%), upper respiratory infection (16.7%), peripheral edema (15.3%), abdominal pain (15.3%), dizziness (13.9%), muscle spasms (13.9%), contusion (13.9%), anemia (12.5%), pneumonia (12.5%), sinusitis (12.5%), and urinary tract infection (11.1%). One CLL patient at the 500 mg BID dose level has experienced a drug-related adverse event of grade 4 thrombocytopenia during Cycle 1 that was assessed as a DLT. The number of patients discontinuing study treatment due to AEs was low (2.4%).Results are summarized for efficacy-evaluable patients treated at the 4 dose levels where at least a partial response (PR) was achieved (750 mg, 1000 mg, 375 mg bid and 500 mg bid) (n = 55). During cycle 1, 89% experienced a ≥ 25% increase in absolute lymphocyte count (ALC), which usually resolved with continued treatment. The table below details the best responses achieved to date. In subjects with del11q, del17p, unmutated IgVH, and no high-risk genomic factors, the PR rate was 42% (5/12), 25% (3/12), 44% (7/16), and 47% (7/15), respectively. Importantly, nodal responses were induced in the majority of subjects receiving BID dosing (375 mg: 67%; 500 mg: 62%) with an overall PR rate of 40%. When achieved, nodal responses were typically observed by cycle 2 and were sustained with continued treatment. Although the sample size is small, subjects treated at 375 mg or 500 mg BID showed continued lymph node size reduction over time from cycle 2 (mean reduction of 42% and 45%, respectively) to cycle 7 (mean reduction of 60% and 71%, respectively). ConclusionCC-292 is well tolerated as an oral daily therapy. Single-agent therapy with CC-292 is sufficient to achieve high nodal and partial response rates in relapsed/refractory CLL subjects, including those with high-risk genomic features. These results support continued development of CC-292 for the treatment of patients with CLL/SLL. Disclosures:Brown:Pharmacyclics: Consultancy; Genentech: Consultancy; Celgene: Consultancy, Research Funding; Emergent: Consultancy; Onyx: Consultancy; Sanofi Aventis: Consultancy; Vertex: Consultancy; Novartis: Consultancy; Genzyme: Research Funding. Off Label Use: The abstract shows scientific information on CC292 which is an investigational product developed by Celgene. This investigational product is not approved by any health authority for any indication. Harb:Celgene: Research Funding. Hill:Celgene: Honoraria, Research Funding. Sharman:Celgene: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Cylene Pharmaceuticals: Consultancy, Research Funding; Avila Pharmaceuticals: Consultancy, Research Funding. Barr:Celgene: Consultancy. Foran:Celgene: Research Funding. Burger:Pharmalytics: Research Funding; Gilead: Research Funding. Mahadevan:Novartis: Speakers Bureau; Millennium: Speakers Bureau. Ma:Genentech: Consultancy; Abbvie: Consultancy. Barnett:Celgene: Employment, Equity Ownership. Marine:Celgene: Employment, Equity Ownership. Nava-Parada:Celgene: Employment, Equity Ownership. Azaryan:Celgene: Employment, Equity Ownership. Mei:Celgene: Employment, Equity Ownership. Kipps:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

A phase I study of nelfinavir concurrent with temozolomide and radiotherapy in patients with glioblastoma multiforme

We conducted a phase I trial to examine the maximally tolerated dose (MTD) of the oral protease inhibitor nelfinavir (NFV) in combination with temozolomide and concurrent radiotherapy in patients with glioblastoma and to gather preliminary data for response. The study was conducted in patients with newly diagnosed glioblastoma after surgical resection. Patients were treated with standard radiotherapy (6,000 cGy to the gross tumor volume), temozolomide (75 mg/m(2) daily) together with daily oral NFV starting 7-10 days prior to chemoradiotherapy continuing for the duration of chemoradiation for 6 weeks. Temozolomide (150-200 mg/m(2)) was resumed 4 weeks after completion of chemoradiotherapy. Two dose levels of NFV were investigated: 625 mg twice daily (bid) and 1,250 mg bid in a cohort escalation design. A total of 21 patients were enrolled. At the maximum tolerated dose, 18 subjects were enrolled to further evaluate toxicity and for preliminary estimate of efficacy for further phase II study. No dose-limiting toxicity was noted at 625 mg bid. At 1,250 mg bid, 3 dose-limiting episodes of hepatotoxicity were noted and one dose-limiting episode of diarrhea. The MTD for this study was 1,250 mg bid. NFV (1,250 mg bid) concurrent with temozolomide and radiotherapy is tolerated in most patients with glioblastoma. At the 1,250 mg bid dose level, patients should be monitored for hepatotoxicity and GI side effects.

Abstract P6-10-05: SU2C Phase 1b Trial of Dual PI3K/ mTOR Inhibitor BEZ235 with Letrozole in ER+/HER2− Metastatic Breast Cancer (MBC)

Abstract Background: Mutations in PIK3CA, the gene encoding the p110alpha subunit of PI3K, have been associated with antiestrogen resistance in ER+ BC. In general, antiestrogen-resistant cancers retain ER and responsiveness to estradiol, suggesting that treatment of ER+/PI3K mutant BC should include PI3K inhibitors plus endocrine therapy. Methods: We are conducting a phase Ib open-label trial of letrozole (2.5 mg/d) with the dual PI3K/ mTOR inhibitor BEZ235 (400 mg BID, sachet formulation) in post-menopausal patients with ER+/HER2 negative MBC. Upon toxicity, BEZ235 was reduced to 400 mg in AM/ 200 mg in PM (dose level 1), and 200 mg BID (dose level 2), in a standard 3+3 de-escalation design. Treatment continues until unacceptable toxicity or disease progression. Tumor assessments are performed every 2 months. All tumor biopsies are being analyzed for PI3K pathway alterations. Results: To date, 9 patients have been accrued; 6 on dose level 1 (400 mg BID) and 3 on dose level 1 (400 mg in AM/ 200 mg in PM). Of note, the latter 3 patients have been on treatment for less than 2 weeks at the time of abstract submission. Median age was 55 years (range 40–65); all patients had disease progression on previous endocrine therapy, and 100% had bone metastases and 30% had visceral metastases. Preliminary toxicities for dose level 1 cohort (400 mg BID) are summarized in the table below. The DLT was grade 3 mucositis, which happened less than 3 weeks of study initiation, in a total of 3 out of 6 patients. All grade 3 mucositis cases improved after BEZ235 interruption for 7 days and subsequent dose reduction. These 3 events triggered activation of the dose level 1 cohort (400 mg AM/ 200 mg PM). The first 3 patients on dose level 1 cohort (2 of which have PIK3CA mutated tumors) had their tumor assessment scans at 8 weeks post treatment initiation; all patients were found to have stable disease. Discussion: The combination of letrozole/BEZ235 is still being evaluated in patients with ER+/HER2MBC. Safety, tolerability and preliminary antitumor activity data will be updated at the meeting. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-10-05.