Dose-limiting Toxicity In Cohort Research Articles

Abstract CT143: Results of combined targeting of prostate-specific membrane antigen (PSMA) with alpha-radiolabeled antibody 225Ac-J591 and beta-radiolabeled ligand 177Lu-PSMA I&T: preclinical and initial phase 1 clinical data in patients with metastatic castration-resistant prostate cancer (mCRPC)

Abstract Background: PSMA is overexpressed by the majority of PC and may be targeted by both antibodies (mAb) and small molecule ligands (SML), each with differing PSMA binding sites, kinetics, and biodistributions. mAbs have long circulating times (exposing organs such a bone marrow) but are too large to target normal tissue luminal PSMA expression in salivary glands, small bowel, and kidney; SMLs rapidly diffuse to all PSMA+ sites and are excreted by the kidneys within hours. Alpha emitters have high potency over a short range whereas beta emitters have lower energy over a significantly longer range. We hypothesized that combining mAb and SML targeting plus combining alpha and beta emitters offered complementary benefits and would be safe and effective. Methods: A series of cell line and xenograft studies were performed to test mAb vs SML vs combo binding, uptake, and efficacy. A phase I/II clinical trial was initiated, enrolling patients with progressive, PSMA+ (by PSMA PET) mCRPC following potent AR pathway inhibition and chemotherapy (or chemo ineligible/refused)[NCT04886986]. The primary endpoint of phase I is assessment of dose-limiting toxicity (DLT) with secondary endpoints of response, progression-free and overall survival, genomic and imaging correlatives, and patient-reported outcomes. Results: Binding studies demonstrated that mAb plus SML binding was additive rather than competitive in LNCaP and CWR22Rv1 cell lines. Uptake of 177Lu-mAb plus -SML in LNCaP, CWR22rv1, and PC3/PSMA xenograft models demonstrated synergism, with 44-65% greater tumor radioactivity in combination than the sum of the individual agents. Intracellular tracking studies indicate that the mAb re-directs SML to lysosomes from recycling endosomes, maintains retention of SML in tumor cells, and, therefore, prolongs intra-tumoral radioactivity exposure. Survival was prolonged in animals receiving 225Ac-mAb plus 177Lu-SML vs either drug alone (or control). Nine men with median age 68 (range 55-87), PSA 140 (2.4-9614) have been enrolled in both of 2 planned dose-escalation cohorts. 89% with bone, 44% lymph node, 22% liver, 22% lung metastases; 88% with detectable CTC count (75% unfavorable). All had at least 1 metastatic lesion with PSMA PET SUVmax > liver SUVmean, with SUVmax of the single hottest lesion ranging from 11.6-69.9. For the primary endpoint, 0 of 3 with DLT in cohort 1, and with follow up ongoing, no DLT has occurred to date in 6 patients in cohort 2. Of evaluable patients, 5 of 6 with PSA decline (8-97% decline). Conclusions: Targeting PSMA with the combination of mAb and SML leads to synergistic radioactivity in preclinical studies. The combination on mAb and SML radiolabeled with alpha and beta emitters appears safe with short-term follow up with phase 2 enrollment planned. Citation Format: Scott T. Tagawa, Edward Fung, Muhammad O. Niaz, Mahelia Bissassar, Sharon Singh, Amie Patel, Angela Tan, Juana Martinez Zuloaga, Sandra Huicochea Castellanos, Jones T. Nauseef, Ana Molina, Cora Sternberg, David M. Nanus, Joseph Osborne, Neil H. Bander. Results of combined targeting of prostate-specific membrane antigen (PSMA) with alpha-radiolabeled antibody 225Ac-J591 and beta-radiolabeled ligand 177Lu-PSMA I&T: preclinical and initial phase 1 clinical data in patients with metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT143.

A phase 1 study in patients with advanced non-small cell lung cancer treated with stereotactic radiotherapy to the primary tumor combined with durvalumab and tremelimumab.

e21121 Background: Cancers can be recognized by the immune system and immunotherapy (ICI) has become an important treatment for lung cancer. Compared to chemotherapy, combining an anti-CTLA-4 and PD-L1 inhibitor increases response- and survival rates independent of PD-L1 status. We hypothesized that adding stereotactic radiotherapy (SBRT) to increase the release of cancer cell antigens might improve treatment results even further. Because of accumulating tumor heterogeneity it may be important to irradiate the primary tumor (addressing trunk mutations), rather than its metastases (branch mutations). We assessed toxicity of adding SBRT to (dual) ICI. Methods: In 3 sequential cohorts, ICI regimes combined with SBRT were studied in stage IIIB/IV NSCLC patients progressing on chemotherapy. All patients were irradiated on an FDG avid part of the primary tumor (1x20 Gy on 9cc) 1 week after the 1st dose of ICI; in case of dual ICI the 1st dose of the 2nd ICI was administered within 1 week following SBRT. Following treatments both ICI were combined. The 1st cohort (n = 3) received durvalumab (D) monotherapy for up to 1 year. The 2nd cohort starting with tremelimumab (T) and the 3rd cohort starting with D (both n = 6) received a combination of D and T (4 cycles) followed by D monotherapy for up to 1 year. The 2nd and 3rd cohort only proceeded when dose limiting toxicities (DLT) occurred in ≤33% of cases in the previous cohort. DLT was defined as any grade ≥3 toxicity that occurred during the first 8 weeks of therapy. Treatment related adverse events (TRAEs) were categorized using NCI CTCAE version 4.3. Descriptive statistics were used to summarize baseline characteristics and TRAEs. Results: Fifteen patients were included from June 2018 to November 2020. Last study visit was in September 2021. Baseline characteristics of the groups were comparable. The median irradiated tumor volume was 9.13 cc (8.98-9.60 cc) with a mean lung dose of 0.44 Gy (0.14-0.73 Gy). The V20 was nihil (0-0.1%) and the V5 1.8% (0-4%). There was 1 DLT in cohort 3 (colitis grade 3). There was 1 low grade TRAE (pneumonitis grade 2) in cohort 1. In cohort 2, 6 low grade TRAEs (CTC 1-2) were observed and 2 high grade (CTC 3) in 1 patient, who discontinued treatment. In cohort 3, 4 low grade and 1 high grade TRAE occurred. Median progression free survival was 2 months, median overall survival 10 months. Conclusions: No additional toxicity was observed by adding SBRT to the primary tumor to (dual) ICI. Clinical trial information: 2017-002797-39. [Table: see text]

Pembrolizumab (pembro) plus binimetinib (bini) with or without chemotherapy (chemo) for metastatic colorectal cancer (mCRC): Results from KEYNOTE-651 cohorts A, C, and E.

3573 Background: Response to antiPD-1 monotherapy is poor in microsatellite stable (MSS)/mismatch-repair proficient (pMMR) mCRC; the combination of antiPD-1 pembro + anti-MEK bini, with or without chemo, may improve upon this limited response. KEYNOTE-651 (NCT03374254) is an open-label phase 1b multicenter trial of pembro + bini (cohort A) or pembro + bini + chemo (mFOLFOX7 in cohort C, FOLFIRI in cohort E) in MSS/pMMR mCRC. Preliminary results from the dose-finding phase at 2 dose levels (DL) of bini are presented. Methods: Patients (pts) had MSS/pMMR mCRC and must have been previously treated with fluoropyrimidine, irinotecan, and oxaliplatin in cohort A, or with fluoropyrimidine + oxaliplatin-based regimen in cohort E; pts were previously untreated in cohort C. Pts received pembro 200 mg Q3W + bini 30 mg BID (cohort A, DL1), pembro 200 mg Q3W+ bini 30 mg BID + mFOLFOX7 Q2W (cohort C, DL1) or pembro 200 mg Q3W + bini 30 mg BID + FOLFIRI Q2W (cohort E, DL1). Bini dose escalation to 45 mg BID (DL2) was planned in cohorts A, C, and E, with a target dose-limiting toxicity (DLT) of 30%. Primary end point was safety (DLT). Secondary end point was ORR. DCR, PFS, and OS were exploratory. ORR, DCR, and PFS were assessed by investigator per RECIST v1.1. Results: Median study follow-up at data cutoff (Oct 15, 2021) was 36 mo (range, 32-43) for cohort A, 17 mo (2-24) for cohort C, and 11 mo (2-25) for cohort E. In cohort A, 1/6 pts (17%) had DLT at DL1; no DLT occurred in 14 pts (0%) at DL2. In cohort A, gr 3/4 TRAEs occurred in 3/6 pts (50%) at DL1 and 8/14 pts (57%) at DL2. In cohort C, 3/9 evaluable pts (33%) had DLT at DL1; thus, bini dose was not escalated to DL2. In cohort C, gr 3/4 TRAEs occurred in 9/11 total pts (82%). In cohort E, 1/5 evaluable pts (20%) had DLT at DL1 and 5/10 evaluable pts (50%) had DLT at DL2. Enrollment was stopped in cohort E, DL2 and bini dose was de-escalated to DL1; 2/4 additional pts (50%) had DLT at DL1 (total 3/9 pts [33%] had DLT in cohort E, DL1). In cohort E, gr 3/4 TRAEs occurred in 5/9 pts (56%) at DL1 and 10/11 total pts (91%) at DL2. No gr 5 TRAEs occurred in any cohort. ORR was 0% in cohort A; limited efficacy was seen in cohorts C and E (Table). Conclusions: Bini could be safely combined with pembro in cohort A. However, with bini + pembro + chemo, the 45-mg dose of bini was not well tolerated and required dose reduction to 30 mg. Addition of bini to pembro + chemo did not improve efficacy; therefore, enrollment was prematurely closed in cohorts C and E. Efficacy by KRAS mutation status will be shown. Clinical trial information: NCT03374254. [Table: see text]

A Phase I Study of CD19 Chimeric Antigen Receptor-T Cells Generated By the PiggyBac Transposon Vector for Acute Lymphoblastic Leukemia

Introduction: Chimeric antigen receptor-modified T cells targeting CD19 (CD19.CAR-T cells) have shown clinical success in patients with hematological malignancies. Despite the encouraging results obtained with this novel therapy, a major concern to its global spread, particularly in developing countries, is its high cost. We developed a method of non-viral gene transfer using piggyBac transposon to reduce the cost of CAR-T therapy. In preclinical study, the median number and transduction efficiency of CAR-T cells obtained from 2x10 7 PBMC in 9 donors were 1.0x10 8 (range, 0.58-1.8x10 8) and 51% (range, 29-73%), respectively. The major subset of CAR-T cells was phenotypically CD8+CD45RA+CCR7+, closely related T-memory stem cells. Ex vivo, CD19.CAR-T cells showed cytotoxic effect on CD19 positive tumor cell lines. In NSG mice model, CD19.CAR-T cells successfully inhibit tumor growth. CAR gene integration sites were determined by inverse polymerase chain reaction and subsequent next-generation sequencing using MiSeq and equally distributed throughout the genome without preference for specific sites. The pre-clinical testing in mouse demonstrated safe toxicity profile at the 50 times dose of CD19.CAR-T cells. We started a human clinical trial to define feasibility, toxicity, maximum tolerated dose and clinical response of CD19.CAR-T cells (jRCTa040190099).Methods: We report the results of cohort 1 of the study in which the safety and efficacy of autologous CD19.CAR-T in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia were evaluated. We engineered autologous T cells via the piggyBac transposon system with CD19.CAR-expression transposon vector and piggyBac transposase-expression vector to express CD19.CAR incorporating CD28 costimulatory domain. We designed this phase I trial using a modified 3 + 3 design to enroll 3-12 patients with relapsed or refractory acute lymphoblastic leukemia in both children and adults. In this study, patients in cohorts 1 (16-60 years old) and 2 (1-15 years old) receive 1 × 10 5 CAR-transduced T cells per kg. Patients in cohorts 3 and 4 (both 1-60 years old) receive 3 × 10 5 and 1 × 10 6 CAR-transduced T cells per kg, respectively. All patients receive 25mg/m 2/d of fludarabine and 250mg/m 2/d of cyclophosphamide for 3 days followed by a single infusion of CAR-T cells.Results: Three patients were enrolled in cohort 1 and infused with 1 × 10 5 CAR-transduced T cells per kg. All patients had previously undergone allogeneic hematopoietic stem cell transplantation. All patients had achieved a hematological complete response with salvage treatment before CAR-T therapy. None of the patients had dose-limiting toxicities (DLT) defined as nonhematological toxicities above grade 4 or cytokine release syndrome (CRS) above grade 4 or graft versus host disease (GVHD) above 4, or grade 3 nonhematological toxicities and GVHD not improved to grade 2 within 4 weeks after CAR-T infusion. There was no occurrence of non-hematological adverse events above grade 3. CRS was observed in one patient (grade 1) who also developed headache due to infiltration of CAR-T cells into the spinal fluid. In two patients, B cell aplasia lasted 2 and 9 months, respectively. Elevation of serum cytokine levels was observed in all patients and the peak time point was 7-21 days after CAR-T cell infusion.Conclusions: CD19.CAR-T cell infusion produced by the piggyBac transposon gene engineering system was safe in cohort 1 of our study. As no patients had DLT in cohort 1, we are enrolling the patients in further cohorts. DisclosuresMurata: MSD: Honoraria; Kyowa Kirin: Honoraria; Sumitomo Dainippon Pharma: Honoraria; FUJIFILM: Honoraria; Toyama Chemical: Honoraria; Novartis: Honoraria; JCR Pharmaceutical: Honoraria; Astellas: Honoraria; Miyarisan Pharmaceutical: Honoraria; Asahi Kasei: Honoraria; GlaxoSmithKline: Honoraria; Celgene: Honoraria; Otsuka Pharmaceutical: Honoraria.

608P - Pembrolizumab (pembro) plus mFOLFOX or FOLFIRI in patients with metastatic colorectal cancer (mCRC): KEYNOTE-651 cohorts B and D

BackgroundPembro, a PD-1 inhibitor, confers durable benefit in many tumor types but has limited efficacy in non–microsatellite instability–high (MSI-high)/pMMR mCRC. Chemotherapies that include 5-fluorouracil (5-FU), oxaliplatin and irinotecan, which are commonly used to treat mCRC, may modulate intrinsic tumor immunogenicity and sensitize tumors to immunotherapy agents. In the phase 1b KEYNOTE-651 study (NCT03374254), pembro + mFOLFOX7 (cohort B) or pembro + FOLFIRI (cohort D) was evaluated in patients with non–MSI-high/pMMR mCRC. MethodsPatients were ≥18 years with non–MSI-high/pMMR mCRC, Eastern Cooperative Oncology Group performance status 0/1, and no prior systemic chemotherapy for stage IV mCRC (cohort B) or 1 prior therapy including a fluoropyrimidine + oxaliplatin-based regimen (cohort D). Patients received pembro 200mg every 3 weeks (Q3W) + mFOLFOX7 (oxaliplatin [85mg/m2]; leucovorin [400mg/m2]; 5-FU [2400mg/m2]) Q2W (cohort B) or pembro 200mg Q3W + FOLFIRI (irinotecan [180mg/m2]; leucovorin [400mg/m2]; 5-FU [2400mg/m2]) Q2W (cohort D). Primary objectives were safety/tolerability and establishment of the recommended phase 2 dose (RP2D); the secondary objective was objective response rate. ResultsAt data cutoff (Feb 18, 2019), 15 patients in cohort B and 16 in cohort D started treatment; median follow-up was 6.8 months (cohort B) and 5.7 months (cohort D). Treatment was discontinued in 4 patients (27%) in cohort B (adverse event [AE], n=1 [7%]; PD, n=3 [20%]) and 9 patients (56%) in cohort D (AEs, PD, patient withdrawal; n=3 [19%] each). There was 1 dose-limiting toxicity in cohort D: grade 3 small-intestinal obstruction. See RP2Ds for cohorts B and D in the Methods section. All patients had ≥1 treatment-related AE (TRAE). Grade 3 TRAEs occurred in 8 patients each in cohort B (53%) and cohort D (50%), most commonly anemia and neutropenia (13% each) in cohort B and neutropenia, diarrhea, fatigue, and leukopenia (13% each) in cohort D. There were no grade 4-5 TRAEs. Efficacy results will be presented. ConclusionsPembro in combination with mFOLFOX7 or FOLFIRI was safe and tolerable in patients with mCRC. Clinical trial identificationNCT03374254; Release date: December 15, 2017. Editorial acknowledgementJacqueline Kolston, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA); Funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Legal entity responsible for the studyMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Array BioPharma. FundingMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Array BioPharma. DisclosureR. Kim: Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly; Research grant / Funding (institution): Eisai. J. Kortmansky: Research grant / Funding (institution): Merck; Research grant / Funding (institution): Roche. L. Wong: Research grant / Funding (institution): Astellas Pharma Global Development, Inc./Astellas US, Inc.; Research grant / Funding (institution): BeiGene, Ltd; Research grant / Funding (institution): Exelixis, Inc.; Research grant / Funding (institution): Merck; Research grant / Funding (institution): NovoCure, Inc.; Research grant / Funding (institution): Pierre Fabre Médicament; Research grant / Funding (institution): PledPharma AB; Research grant / Funding (institution): SynCore Biotechnology Co., Ltd.; Research grant / Funding (institution): Halozyme, Inc.; Research grant / Funding (institution): Pharmacyclics, Inc.; Research grant / Funding (institution): TESARO; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Array. M. Tehfe: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Celgene; Honoraria (self): Ipsen; Advisory / Consultancy: BMS; Advisory / Consultancy: Takeda; Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Taisho. J.J. Li: Full / Part-time employment: Merck & Co., Inc. M. Lee: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. C. Mayo: Full / Part-time employment: Merck & Co., Inc. P. Marinello: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. E. Chiorean: Advisory / Consultancy: Ipsen; Advisory / Consultancy: Eisai; Advisory / Consultancy: Halozyme; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Array; Advisory / Consultancy: Five Prime; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): AstraZeneca; Travel / Accommodation / Expenses: Halozyme; Research grant / Funding (institution): Merck; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Ignyta/Roche; Research grant / Funding (institution): Stemline; Research grant / Funding (institution): Macrogenetics. All other authors have declared no conflicts of interest.

A Multicenter Open-Label, Phase 1b/2 Study of Ibrutinib in Combination with Lenalidomide and Rituximab in Patients with Relapsed or Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL)

A Multicenter Open-Label, Phase 1b/2 Study of Ibrutinib in Combination with Lenalidomide and Rituximab in Patients with Relapsed or Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL)

Phase I dose-escalation clinical trial with 5-imino-13-deoxydoxorubicin in cancer patients.

2575 Background: 5-imino-13-deoxydoxorubicin (DIDOX; GPX-150) is a doxorubicin (dox) analog modified in two locations to prevent formation of a) cardiotoxic metabolites and b) reactive oxygen species. In a rabbit model comparing the cardiotoxicity of dox vs. DIDOX, chronic doses of each caused similar myelosuppression, but only dox caused cardiotoxicity as assessed by echocardiography and histopathology scoring. In view of the non-cardiotoxic nature of DIDOX along with its anticancer efficacy in preclinical studies, DIDOX was entered into a Phase I, open-label, non-randomized dose-finding study in up to 30 patients with solid tumors. Methods: Inclusion criteria included progressing solid tumors and cardiac ejection fraction (CEF) 110% of lower limit of institutional normal (assessed by MUGA). There are 8 dose cohorts and up to 8 cycles/cohort, dosing (iv) once every 3 weeks with an accelerated titration dosing design at the three lowest cohorts. Cohort A =14, B=28, C=56, D=84, E=112, F=150, G=200, and H=265 mg/m2/cycle. Dose was escalated to next dose level if < 1 dose limiting toxicity (DLT) is reported. Maximum tolerated dose (MTD) will be exceeded when 2 or more patients in a cohort elicit DLT; the next lower dose is defined as the MTD. DLT occurs when a decrease in CEF is grade 2 or higher, or grade 4 neutropenia lasts > 5 days. Results: Cohorts A-G have been completed. Number of patients for the cohorts are: A=1, B=1, C=1, D=4 E=3 F=3 G=4, and H = 2 (with 4 more to be enrolled in H). No decrease in CEF occurred in any cohorts. There were no DLTs in cohorts A-G. One patient in H had neutropenia grade 4 for 11 days (a DLT). Another patient in H had neutropenia grade 4 for 4 days. There was no disease progression at the completion of dosing for 6 of the 12 patients in cohorts E-H. In contrast, all 7 patients had disease progression in cohorts A-D. Conclusions: No cardiotoxicity was observed in any patient. No DLT was observed in cohorts A-G. With one DLT in cohort H, one more DLT will define MTD for DIDOX at 200 mg/m2. At higher DIDOX doses (E-H), 6 of 12 patients showed no disease progression. (IND No. 77,051). Clinical trial information: NCT00710125.

822P - A Phase I Dose Escalation Study Investigating Dovitinib and Everolmus in Combination in Metastatic Clear Cell Renal Cancer Patients who have Previously Failed VEGF Targeted Therapy

ABSTRACT Introduction Both dovitinib and everolimus are agents used, or under investigation in patients with renal cancer refractory to VEGF targeted therapy. It is potentially attractive to use these agents in combination in patients with VEGF TKI refractory disease. Together they target mTOR, VEGF and FGF-2. The purpose of this study is to establish a dose for this combination to take forward in randomised trials. Method This phase I study (EUDRACT 2010-021250-19) followed a classic dose escalation 3 + 3 designed. Sequential patients with metastatic clear cell renal cancer, who had previously failed VEGF tyrosine kinase inhibitors were included. Patients received fixed doses of drug in each escalating cohort (maximum n = 6) until dose limiting toxicity (DLT) was reached. DLT included grade 3 toxicity during the first 6 weeks of therapy. If 2 episodes of grade 3 or more toxicity occurred in a specific cohort the DLT cohort had been reached. The study has appropriate ethical approval. Assement of response and progression free survival was by RECIST v1.1 Results Patients were entered into 2 cohorts before DLT occurred (cohort 0: dovitinib 200 mg/everolimus 5mg [n = 6]; cohort 1: dovitinib 300 mg/everolimus 5mg [n = 3]) . DLT in cohort 1 included grade 3 fatigue (2/3) after 2 and 3 week of therapy. In cohort 0 the following toxicity was identified: Lethargy grade 2 3/6 and 3 1/6; Diarrhoea Grade 2 2/6 and 3 0/6 mucositis; grade 2 0/6 and 3 0/6; nausea/vomiting grade 2 0/6 and 3 1/6, pulmonary fibrosis grade 2 1/6 3 0/6 . Grade 3 toxicity after the first 6 weeks of therapy included pulmonary fibrosis 1/6, lipid abnormalities 2/6. Overall 1 patient (11%) had a partial response to therapy. Of the 5 patients who did not stop therapy during the first 6 weeks due to toxicity, 3 continued for 6 months or more without progression. Conclusion The maximum tolerable dose for this combination was dovitinib 200mg and everolimus 5mg. This dose is being taken forward in an expansion cohort which will explore efficacy. Disclosure T.B. Powles: Novarits Has supplied an educational grant for this project. Advisroy role for Novratis. S. Chowdhury: Advisory role. All other authors have declared no conflicts of interest.

Abstract B58: Phase I study of the IGF-1R antibody ganitumab (AMG 479) in combination with everolimus in patients with advanced solid tumors.

Abstract Background: Preclinical data suggests the combination of IGF-1R inhibitor Ganitumab and mTOR inhibitor everolimus may increase anti-tumor activity compared to each agent alone. Therefore we evaluated the maximum tolerated doses/recommended phase II dose for the doublet combination, Ganitumab (G) plus Everolimus (E) followed by an expanded cohort to better understand the safety and tolerability profile. Methods: For dose escalation, eligible patients had advanced solid tumors with adequate organ function and no increased risk for class-related toxicities. G was given intravenously, and E was orally administered; cycle length was 28 days. G was dosed at 12 mg/kg every 14 days; E was dosed at 5 mg daily in cohort one and 5 mg three times weekly in cohort −1. An intermediate dose of E at 5 mg five times weekly was added to better maximize dose intensity. Dose limiting toxicity (DLT) was assessed in cycle 1. Results: Dose escalation is complete with 17 subjects evaluable for DLT toxicity and 16 evaluable for efficacy. Two out of 5 subjects experienced DLTs in cohort one due to dose holdings related to grade 3 hematologic toxicities: thrombocytopenia and neutropenia plus thrombocytopenia. No DLTs were observed out of 6 subjects in cohort −1; one DLT was observed out of 6 subjects in the intermediate cohort due to dose holding related to grade 2 intolerable skin rash and oral mucositis. Possible grade 3 treatment-related adverse events included neutropenia, thrombocytopenia, elevated AST/ALT, hypertriglyceridemia, vomiting and erythema multiforme minor. There were no grade ≥4 treatment-related toxicities. One non treatment- related death was due to disease progression. Two subjects had clinically significant skin rashes which resulted in protocol discontinuation. Twelve subjects have available efficacy data; 4 subjects have not yet been restaged. Two subjects with refractory NSCLC achieved a complete response. Six additional subjects had stable disease as best response. Conclusion: The recommended phase II dose for this doublet combination is G at 12 mg/kg every two weeks and E at 5 mg five times weekly. At this dose, this novel regimen is well-tolerated with potential activity in NSCLC. Enrollment in the expanded cohort has started. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B58.

A phase I, single-institution open-label, dose-escalation trial with an expansion cohort evaluating the safety and tolerability of AZD6244 and IMC-A12 in subjects with advanced solid malignancies.

TPS156 Background: IGF-1 receptor (IGF1-R) phosphorylation leads to activation of the PI3K and Raf/MEK/ERK pathways and plays a central role in the regulation of proliferation, survival, differentiation, and apoptosis. Significant crosstalk exists between the two pathways and treatment of select cell lines with a MEK inhibitor and an IGF1-R inhibitor has been shown to cause greater inhibition of growth than either agent alone. IMC-A12 (I) is a recombinant human monoclonal antibody directed IGFI-R; it blocks interaction between IGF-1R and its ligands, IGF-I and -II. I has demonstrated tumor growth inhibition in a wide range of in vitro and in vivo human cancer. AZD6244 (A) is a highly selective, non-competitive MEK 1/2 inhibitor that has had similar success in vitro and in vivo in cancer models of various solid tumors. In vivo studies have demonstrated the most potent inhibition of cell growth in cell lines harboring RAS and BRAF mutations. Phase I/II studies have shown both agents to be tolerable as single agents and suggested modest efficacy in various cancer types. Methods: A phase I, open label, dose escalation trial with I+A is currently accruing pts with advanced malignancies. The study is a standard 3+3 design with an expansion cohort of 15 pts for correlative endpoints and PK studies. Pts will be treated with A at 50 mg po BID, then 75 mg po BID; I at 12mg/kg q2week held constant. The first 2 cohorts have accrued with a single dose-limiting toxicity in cohort 2. The expansion cohort will start accrual in February 2011. Eligibility includes advanced solid tumor, good end organ function and performance status with exclusion for poorly controlled diabetes or growth hormone abnormalities. The primary objective is to determine the safety and tolerability of the combination and to determine the MTD. Secondary objectives include assessing preliminary efficacy as defined by RECIST criteria and exploration of PK/PD endpoints. Serial tumor biopsies will be evaluated for changes in signaling in the IGF pathway, including p-ERK, p-Akt and RAS. RAS and RAF mutation sites will be sequenced in order to correlate with PD endpoints and disease response.

Abstract P3-14-10: A Dose-Escalation Study of Trastuzumab-DM1 (T-DM1), Paclitaxel (T), and Pertuzumab (P) in Patients with HER2-Positive, Locally Advanced or Metastatic Breast Cancer (MBC) Previously Treated with a Trastuzumab-Containing Regimen

Abstract Background T-DM1 is an antibody-drug conjugate that combines the biological activity of trastuzumab with targeted delivery of an anti-microtubule agent to HER2-expressing cancer cells. T-DM1 monotherapy is effective and well tolerated in pts with pretreated HER2-positive MBC. Nonclinical data suggest synergy for the combination of T-DM1 with taxanes as well as with P. Methods This 3+3 design phase Ib study (T-DM1 4652g) investigates tolerability and dose-limiting toxicities (DLTs) for the combination of T-DM1 (q3w and q1w), T (q1w) and P (q3w). Part 1 consisted of q3w T-DM1 and q1w T dose cohorts. In Part 2, P is added to the MTD of Part 1. In Part 3, q1w T-DM1 will be evaluated. Each cycle is comprised of T-DM1 on day 1, and T on days 1 (day -1 for cycle 1 only), 8, and 15. P (840 mg load followed by 420 mg q3w) is given on day 1 when applicable. Pts were monitored for DLTs for 23 days before determining the next cohort dose level. Results Parts 1 and 2 have completed enrollment with 21 pts. Results reported here are from 14 pts in Part 1, who had finished the DLT observation period as of Mar 30, 2010. The median age was 56 yrs and the median number of prior systemic therapies excluding hormonal therapy was 10 (range 5-23). All pts had received prior therapy with trastuzumab, 13 pts had prior taxane and 11 pts had prior lapatinib therapy. Pts received a median of 4.5 and 11 doses of T-DM1 and T, respectively (range 1-10 and 1-29, respectively). Two pts experienced DLTs in Cohort 1, at T-DM1 2.4 mg/kg q3w and T 65 mg/m2 q1w (n=5); a gr 3 AST/ALT elevation, and a gr 3 dehydration secondary to nausea and vomiting. Therefore the next cohort (Cohort A) opened at a reduced T-DM1 dose, 2.0 mg/kg q3w with T 65 mg/m2 q1w (n=3), where no DLT was observed. In Cohort B (T-DM1 2.0 mg/kg q3w, T 80 mg/m2 q1w, n = 6), 1 pt experienced DLT; a gr 3 neutropenia. Six SAEs in 3 pts have been reported: gr 2 vomiting (considered related), gr 3 dehydration (considered related), gr 3 cellulitis, gr 3 muscular weakness, gr 3 interverterbral disc protrusion, and gr 3 hypersensitivity (considered related). One pt discontinued due to gr 2 thrombocytopenia. Six pts experienced AEs that led to discontinuation of T alone. The preliminary PK assessment suggests a low potential for PK-based T-DM1 T interaction with combination therapy. Overall, 2 objective responses (confirmed) and 4 additional partial responses (unconfirmed) were observed from limited follow-up. Five of these 6 pts remain on study. Conclusions The combination of T-DM1 and T are encouraging given the observed responses. In these extensively pretreated pts with a median of 10 prior therapies, the MTD has been established for q3w T-DM1 at 2.0 mg/kg in combination with T 80 mg/m2, at a dose of T-DM1 well below the single agent dose of 3.6 mg/kg. Maximizing the dose of T-DM1 will be further explored in combination with T and P. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-10.

Phase I Trial of the Combination of Lenalidomide, Thalidomide and Dexamethasone In Relapsed/Refractory Multiple Myeloma

AbstractAbstract 1948 Background:The combination of lenalidomide (Len) and dexamethasone(D) have demonstrated overall response rates (ORR) of 60% in relapsed/refractory multiple myeloma (RRMM). The three drug combination of Len/Thalidomide/D has not previously been evaluated in RRMM. The ORR with LenD with prior Thalidomide(Thal) is 40–50%, while the ORR with ThalD after prior Len is < 20%. Preclinical studies have demonstrated Len resistance is mediated via the wnt-β-catenin pathway which is modulated by Thal. The minimal overlapping side effect profile and differing mechanism of action of Len and Thal and preclinical data provided the rationale for the combination of Len/Thal/D in an attempt to improve RR and overcome lenalidomide resistance. The aim of this study was to determine the tolerability, maximum tolerated dose (MTD) and evaluate preliminary activity. Methods:Patients(pts) with relapsed/refractory myeloma with ≥ 1 line of therapy were eligible with adequate hematology, cardiac, pulmonary, and renal function. Patient were eligible regardless of prior Imid exposure or Imid refractory disease, enrolled in 3 dose cohorts(C), C1: Len 15 mg/Thal 100 mg/Dex, C2:Len 25 mg/Thal 100 mg/Dex, and C3: Len 25 mg/Thal 200/Dex. Dexamethasone was dosed in pulse dose fashion cycles 1–2 and reduced to weekly Dex in cycles 3 and beyond. Pts were treated until disease progression or toxicity. All patients received anticoagulation with warfarin or low molecular weight heparin. Results:18 patients with median 3 prior lines of therapy (range: 1–6) were enrolled, age 67 (range: 52–81), male/female: 13/5; 3 in cohort 1, 6 in cohort 2 and 9 in cohort 3. There were no dose limiting toxicity (DLT) in cohort 1 (0/3), 1/6 DLT in cohort 2 and 2/8 DLT in cohort 3 (1 pt was unevaluable for DLT due to disease progression within cycle 1 and removed prior to completing cycle 1). The DLT in cohort 2 was due to steroid induced toxicity, requiring reduction in dex dosing in cycle 1. The DLT in cohort 3 included one patient with G3 rash due to thalidomide and asymptomatic G2 atrial fibrillation (a. fib) and a second patient with G3 hypertensive crisis and volume overload due to dexamethasone. Other toxicity included a patient with new onset symptomatic a fib in Cohort 3 (during cycle 2, therefore not a DLT) with concurrent newly diagnosed cardiac amyloidosis, and non-neutropenic fever and pneumonia in patient in Cohort 2. Among the 8 patients in C3 who received > 1 cycle, 5 required dose reduction of Thal to 100 mg. No DVT/PE were observed with use of anticoagulation. No G3/4 peripheral neuropathy has been observed.13 patients were evaluable for efficacy (6 unevaluable: 1 withdrew consent after cycle 1, 4 patients in cycle 2 currently and responses not repeated/confirmed). Among the 13 evaluable patients the ORR (> PR) was 92%, 2 nCr, 3 VGPR, 7 PR and 1 with PD in cycle1. Among the 13 evaluable, 6/13 patients had prior thal, 10/13 autologous stem cell transplant, 9/13 prior Len and 8 patients were lenalidomide refractory. Among the 8 patients with Len refractory disease (4 had prior thal), the ORR was 88%, with 1 VGPR, 6 PR, and 1 PD in cycle 1. 4 pts, all with Len refractory disease, have discontinued therapy due to progressive disease after cycle 1, 4, 4, 6 (after initial PR to therapy), the other 4 remain on trial on cycle 3, 5, 7 and 9. Conclusions:The maximum recommended dose is lenalidomide 25 mg/thalidomide 100 mg/dex due to the DLT observed and need for dose reductions in thalidomide. The combination is well tolerated with only 1 pt discontinued therapy due to toxicity (a fib) and 4 pts discontinued secondary to PD. The very high ORR of 92% was much higher than seen with two drug regimen of Len/Dex. The preserved superior activity in lenalidomide refractory disease, supports the modulation of lenalidomide resistance with thalidomide, however a phase 2 trial is open and additional pts at cohort 2 will be enrolled to further evaluate the activity of this combination. Disclosures:Shah:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Novartis: Research Funding. Orlowski:Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding. Wang:Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: Research Funding. Weber:novartis-unpaid consultant: Consultancy; Merck- unpaid consultant: Consultancy; celgene- none for at least 2 years: Honoraria; millenium-none for 2 years: Honoraria; celgene, Millenium, Merck: Research Funding.

A phase I open-label study of escalating-dose oral cyclophosphamide (CTX), docetaxel (D), zoledronic acid (ZA), and high-dose calcitriol (HDC) for castration-resistant prostate cancer (CRPC).

e15079 Background: HDC is a biological agent with activity either alone or in combination in CRPC. Preclinical studies have demonstrated that HDC is synergistic with other cytototoxic agents such as D and oral CTX. Methods: Eligible patients (pts) had progressive, metastatic, chemo-naive CRPC with ECOG 0 or 1. Three pts were treated in each cohort, expanded by 3 pts if a dose-limiting toxicity (DLT) was observed in one pt. If no DLT occurred after all pts completed 1 cycle in a cohort, pts were enrolled at the next dose level. If a DLT was seen in 2 pts, the dose level was closed. D was given I.V. on day 1 with ZA 4mg I.V. at the dose of 60 mg/m2 in the first cycle and escalated to 70 mg/m2 for the next cycles if no DLT occurred. HDC was given P.O. at a fixed dose of 50mcg divided in 4 doses on day 0. Oral CTX was given on days D1-10 and dose levels were: cohort 1 50mg/d; cohort 2 100mg/d and cohort 3 150mg/d. Cycles were given every three weeks. Efficacy was explored as: maximal confirmed PSA decline; partial or complete response (PR+CR) by RECIST criteria and/or changes in bone scan. Results: Fourteen pts were enrolled to complete the dose-finding phase. Characteristics included median age of 68 yrs (range 55-81) and median baseline PSA of 74.6 ng/mL (range 11-571). DLTs by dose level are summarized as: cohort 1, DLT in 1 of 6 pts (febrile neutropenia (Gr) 4); cohort 2, DLT in 1 of 4 pts (neutropenia (Gr) 4); and no DLT in cohort 3. A pt in cohort 3 had acute myocardial infarction probably not related to therapy. Preliminary measures of efficacy by method of assessment and cohort assignment are summarized (Table). Conclusions: We conclude that the D 70 mg/m2, HDC 50 mcg, ZA 4mg every three weeks in combination with oral CTX 50mg (cohort 1) and 100mg (cohort 2) on days1-10 is safe and demonstrates anticancer efficacy. Cohort 1 Cohort 2 Cohort 3 Median # cycles (range) 5.5 (2-10) 5.5 (1-8) 4 (2-7) PSA decline > 30% 3/6 3/4 3/4 > 50% 3/6 2/4 3/4 RECIST PR+CR 2/4 2/4 2/4 Bone Stable 6/6 4/4 4/4 No significant financial relationships to disclose.

Initial Results of a Phase I Dose-Escalation Trial of Concurrent and Maintenance Erlotinib and Reirradiation for Recurrent and New Primary Head-and-Neck Cancer

To present the first report of a Phase I trial evaluating concurrent and maintenance erlotinib and reirradiation in patients with recurrent or secondary primary head-and-neck cancer (HNC). Patients with recurrent or new primary HNC with an interval of at least 6 months since prior radiation were eligible. Patients were treated in 3 sequential cohorts: Cohort I, 100 mg of erlotinib daily with reirradiation at 61.6 Gy in 28 fractions; Cohort II, 150 mg of erlotinib with 61.6 Gy in 28 fractions; and Cohort III, 150 mg of erlotinib with 66 Gy in 30 fractions. Maintenance erlotinib started immediately after reirradiation at 150 mg daily and was continued for 2 years or until disease progression or dose-limiting toxicity. Dose-limiting toxicities were defined as any Grade 4 or 5 toxicity or a toxicity-related delay in radiation therapy of greater than 7 days. Fourteen patients were accrued, 3 to Cohort I, 4 to Cohort II, and 7 to Cohort III. Thirteen patients were evaluable for toxicity. Median follow-up was 8.4 months overall and 15.1 months for surviving patients. One patient had a dose-limiting toxicity in Cohort III. This patient declined initial percutaneous endoscopic gastrostomy tube placement, was hospitalized with Grade 3 dysphagia and aspiration, and required a delay in radiation therapy of greater than 7 days. No Grade 4 acute toxicity was observed. Acute Grade 3 toxicity occurred in 9 of 13 patients. No erlotinib-related toxicity of Grade 3 or greater was observed during maintenance therapy. One patient had Grade 5 carotid hemorrhage 6 months after reirradiation, and another patient had Grade 3 osteoradionecrosis. Reirradiation (66 Gy in 2.2 Gy fractions) with concurrent and maintenance erlotinib (150 mg daily) for recurrent or new primary HNC is feasible.

Phase 1 dose-escalation study of 17-allylamino-17-demethoxygeldanamycin (17AAG) in combination with irinotecan in patients with solid tumors

3533 Background: 17AAG is an inhibitor of the molecular chaperone Hsp90. Pre-clinical studies from our laboratory showed that treatment of cancer cells with 17AAG caused depletion of two critical checkpoint kinases, Chk1 and Wee1, resulting in abrogation of the G2/M checkpoint triggered by topoisomerase I poison, and selective induction of apoptosis in p53-defective cells. Methods: We initiated a phase 1 study of irinotecan (CPT) and 17AAG to determine the maximally tolerated doses (MTD) and tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of the combination. During the dose-escalating phase, patients (Pts) received CPT over 30 min followed by 17AAG over 2 hrs once weekly for two weeks in a 21-day cycle. At the MTD, Pts underwent post-treatment tumor biopsy for PD biomarker analysis after CPT only during week 1 and after the combination during week 2. Results: 22 Pts (median age 53; range 32–73; median KPS 80) with a wide spectrum of solid tumor types were enrolled. Four Pts developed dose-limiting toxicity in cohort 4 (100 mg/m2 CPT and 375 mg/m2 17AAG) including nausea, vomiting, diarrhea, and pulmonary embolism. The PKs of 17AAG and its metabolite 17AG were not affected by the co-administration of CPT. Although no CR/PR’s by RECIST criteria have been seen, minor responses were observed in CPT-naive Pts with pancreas (2), breast (1), and high grade neuroendocrine tumor (1). Pts are currently enrolled to the MTD expanded cohort for further assessment of tolerability and PD analysis. So far, paired tumor biopsies have been successfully obtained in 8/8 Pts and samples will be analyzed for p53 status, Hsp90 client protein depletion, G2/M checkpoint abrogation, and apoptosis. Conclusions: The combination of 17AAG and CPT can be given to Pts with acceptable toxicity. The recommended phase II dose of the combination is 100 mg/m2 CPT and 300 mg/m2 17AAG. (Supported by ASCO CDA and NCI K08 awards) No significant financial relationships to disclose.

Pharmacologically derived schedule of flavopiridol has significant efficacy in refractory, genetically high risk chronic lymphocytic leukemia (CLL)

6516 Background: Promising pre-clinical activity with flavopiridol in CLL was followed by disappointing clinical trial results. Differential protein binding of flavopiridol in pre-clinical studies may have misdirected the target concentration and administration schedule in CLL trials. Methods: We initiated a phase I study based on pharmacokinetic (PK) modeling showing that 1.5–2.0 μM flavopiridol for 4–6 hours was necessary for anti-CLL activity in vitro with 10% human serum. A 30 minute loading dose followed by a 4 hour infusion every 4 of 6 weeks was pursued. Eligibility included refractory/relapsed CLL, intact organ function, and performance status of ≤ 2. Results: Fifty-six pts have been enrolled ( Table ) with a median of 4 prior therapies, and most fludarabine-refractory. Dose-limiting toxicity in cohort 2 was tumor lysis syndrome (TLS). Cohort 1 was expanded with aggressive TLS prophylaxis. Of 20 pts in cohort 1, 8 (40%) had a partial response (PR) with a median response duration exceeding 12 months. The 0.5 and 4.5 hr Cmax were 2.08 μM and 0.96 μM. PK modeling showed that higher dose in the 4-hr infusion would achieve desired 4.5 hr Cmax. This escalation was done in cohorts 3 and 4 ( Table 1 ) with acceptable toxicity. In cohort 3, 19 pts enrolled with 14 pts being dose escalated. Improved cytoreduction was seen in most pts with dose escalation. Ten (53%) of pts attained a PR. The 0.5 and 4.5 hr Cmax was 1.95 μM and 1.54 μM in cohort 3;dose escalation continues in cohort 4. WBC of ≥ 200 × 109/L was associated with TLS (5 of 8 pts) versus those with WBC &lt; 200 × 109/L (1 of 34 pts). As such, cohort 4 excludes pts with WBC ≥ 200 × 109/L for safety. Currently there are 14 pts in cohort 4 with only 1 case of TLS. Response assessment for cohort 4 is underway; activity appears similar to cohort 3. Conclusions: Flavopiridol with this PK directed schedule has significant clinical activity independent of the presence of del(17p13.1) and is one of the most active agents in clinical trials for CLL. [Table: see text] No significant financial relationships to disclose.