ASCO 12 Annual Meeting, June 1-5, 2012, Chicago, Illinois, USA
CRPC (Vaccines, Abiraterone, Cabazitaxel, Sipuleucel-T, MDV3100, ADT, other treatments,)
Vaccines
Phase I trial of NY-ESO-1/LAGE1 peptide vaccine for metastatic castration resistant prostate cancer (mCRPC).
Abstract No:4643
Citation:
J Clin Oncol 30, 2012 (suppl; abstr 4643)
Author(s): Teresa Gray Hayes, Guru Sonpavde, Mingjun Wang, Yicheng Wang, Teresa Joe, Martha P. Mims, Michael M. Ittmann, Thomas M. Wheeler, Adrian P. Gee, Rongfu F Wang; Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, TX; Texas Oncology, Michael E. DeBakey VA Medical Center, and Baylor College of Medicine, Houston, TX; The Methodist Hospital, Houston, TX; Baylor College of Medicine, Houston, TX; Department of Pathology, Baylor College of Medicine, Houston, TX
Abstract:
Background: The NY-ESO-1 and LAGE-1 antigens are amplified in malignancies including prostate cancer. Preclinical induction of immune responses and anti-tumor activity has been demonstrated upon administration of these peptides. A phase I/II clinical trial evaluated the feasibility of a combined HLA class-I and class-II peptide vaccine in mCRPC. Methods: Men with progressive mCRPC, Performance Status ≤2, PSA ≥10 ng/ml and had appropriate HLA class I (A2) and class II haplotypes (DR4, DP4, DR13) were eligible. Three groups with 3 patients each received the vaccine subcutaneously every 2 weeks for 6 doses. Group 1 was treated with a peptide directed at a HLA class I haplotype (HLA A2), Group 2 was treated with a peptide reacting to a HLA class II haplotype (DR4, DP4, or DR13), and Group 3 received peptides directed at both Class I and II haplotypes. Group I and Group II received 1 dose of 1000 mcg and Group III received doses of 1000 mcg for each of 2 peptides. Androgen-deprivation was continued. Results: Of 14 patients enrolled, all were evaluable for toxicities and 9 patients completed all 6 treatments per amended protocol and were evaluable for efficacy. The median baseline PSA was 85.19 ng/ml. Four patients were chemo naive and 5 were post-docetaxel. One patient had a grade 5 event (myocardial infarction) unlikely therapy-related. Potential therapy related toxicities were local grade 1 injection site erythema (n=5), fatigue (n=2), flu-like symptoms (n=1), myalgias (n=1), anorexia (n=1), nausea (n=1) and leukocytosis (n=1). The median PSA doubling time pre-therapy and during therapy were 3.1 and 4.92 months, respectively. The PSA-DT was prolonged compared to baseline in 6 patients, including a negative PSA slope in 2 patients. Antigen-specific immune response determined by ELISPOT was observed, and its association with slowing of PSA-doubling time will be further examined. Conclusions: In men with mCRPC, HLA class-I and/or class-II restricted NY-ESO-1 and LAGE-1 peptides administered subcutaneously demonstrated excellent tolerability, slowing of PSA doubling time and antigen-specific immune responses. Further development of peptide vaccines alone or in combination with other regimens may be warranted.
Interim analysis of a phase II randomized clinical trial of samrium-153 (Sm-153) with or without PSA-TRICOM vaccine in metastatic castration-resistant prostate cancer after docetaxel.
Abstract No:2526
Citation:
J Clin Oncol 30, 2012 (suppl; abstr 2526)
Author(s): Christopher Ryan Heery, Ravi A. Madan, Marijo Bilusic, Joseph W. Kim, Nishith K. Singh, Myrna Rauckhorst, Clara Chen, William L. Dahut, Walter Michael Stadler, Robert S. DiPaola, Mark N. Stein, James W. Hodge, Jeffrey Schlom, James L. Gulley; Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD; Laboratory of Tumor Immunology and Biology and Medical Oncology Branch, National Cancer Institute, Bethesda, MD; Medical Oncology Branch, National Cancer Institute, Bethesda, MD; National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD; Department of Nuclear Medicine, Clinical Center, National Institutes of Health, Bethesda, MD; The University of Chicago, Chicago, IL; Cancer Institute of New Jersey, New Brunswick, NJ; Laboratory of Tumor Immunology and Biology, National Cancer Institute, Bethesda, MD; Laboratory of Tumor Immunology and Biology, Center for Cancer Research, Bethesda, MD
Abstract:
Background: A prior randomized, placebo-controlled, multi-center phase 2 trial of PSA-TRICOM (PROSTVAC) demonstrated an overall survival benefit. Sm-153 is a radiopharmaceutical that targets osteoblastic bone lesions. Preclinical data indicated that Sm-153 could alter tumor phenotype, causing upregulation of Fas, MHC Class I, and tumor-associated antigens, making tumor cells more amenable to immune-mediated killing. Methods: This is a phase 2 multi-center trial design intended to randomize 68 patients (pts) to Sm-153 with or without PROSTVAC. Eligibility included castrate resistant prostate cancer bone metastases, no visceral disease, prior docetaxel, ECOG ≤2, and normal organ function. Sm-153 was given at 1mCi/kg IV on day 8 and then every 12 weeks. PROSTVAC was given on days 1, 15, 29, then every 4 weeks. The 1° endpoint is a comparison of progression-free survival at 4 months (mo) utilizing PCCWG, but not PSA criteria. 68 patients will provide 80% power to detect a difference of 15% vs. 40% without progression at 4 mo with a one-tailed alpha = 0.10 assuming Fisher’s exact test comparing these fractions as the primary method of analysis. 2° endpoints are OS, ORR, PSA changes, immunologic, toxicity, and palliation. Reported here is the result of a pre-specified interim analysis, which required ≥20% conditional power to detect 15% vs. 40% without progression at 4 months for the trial to continue. Results: Of 37 enrolled pts, 3 were not evaluable for PFS. PFS and PSA findings are found below. Hematologic toxicities (anemia, thrombocytopenia, neutropenia, or lymphocytopenia) are most common, with grade 3 or 4 thrombocytopenia occurring in 22% and 26% of treatment cycles on Arms A and B, respectively. The conditional power for the comparison of fractions without progression at 4 mo is 77%. Conclusions: This interim analysis suggests the combination of PROSTVAC and Sm-153 is well tolerated with similar toxicity profile to Sm-153 alone. The early indication of improved TTP warrants continued study accrual.
/ Sm-153(A) / Sm-153 + PROSTVAC
(B) /
PFS
At 4 mo / 2/17 (11.8%) / 5/17 (29.4%)
Median PFS days / 60 / 117
Pt # confirmed PSA decline
≥ 30% / 0 / 4
≥ 50% / 0 / 2
Prospect: A randomized, double-blind, phase III efficacy trial of PROSTVAC.
Abstract No:TPS4699
Citation:
J Clin Oncol 30, 2012 (suppl; abstr TPS4699)
Author(s): Olga Bandman; BN ImmunoTherapeutics, Mountain View, CA
Abstract:
Background: PROSTVAC is a candidate cancer vaccine comprised of two recombinant poxviral vectors: vaccinia (V) and fowlpox (F), each with insertions of four human genes: PSA and three costimulatory molecules (TRICOM) - LFA-3, B7.1 and ICAM-1. This off the shelf vaccine demonstrated a statistically significant overall survival (OS) benefit of 8.5 months while displaying a favorable side effect profile in patients (pts) with asymptomatic to minimally symptomatic prostate cancer (mCRPC) in a randomized, placebo –controlled 122-pt Phase II trial. Data from this Phase II trial supported the design of a Phase III protocol that will rigorously test the hypothesis of OS benefit, as well as expand our understanding of immune system response to cancer vaccines. Methods: 1200 pts will be randomized in a double-blind fashion to three arms: PROSTVAC, PROSTVAC+GM-CSF, or Placebo, at 1:1:1 ratio. A five-month treatment regimen will include a priming vaccination with PROSTVAC-V, and six booster vaccinations with PROSTVAC-F. Eligible pts will have asymptomatic or minimally symptomatic mCRPC, and progression despite androgen ablation and be chemotherapy-naïve. Pts with rapidly progressing disease will be excluded, as well as pts with risk factors for developing vaccinia-associated complications. The projected trial size is 400 pts per arm for at least 85% power. Primary endpoint is OS. The final analyses will be event-driven and will compare each active arm independently with placebo. Pts will be followed for 12 months after the projected number of events in each arm is realized. Secondary endpoint is proportion of event-free pts at 6 months compared to placebo. A number of exploratory endpoints are planned, including immune response to immunizing antigen, non-vaccine-contained prostate antigens, tumor-associated antigens; changes in baseline biomarker levels and CTC levels, as well as characterization of T cell subpopulations. The thorough immune monitoring program would provide basis for future studies on the effects of cancer immunotherapy on immune system and facilitate search for potential biomarkers of such effects. The trial is currently open for enrollment. ClinicalTrials.gov registry number: NCT00450463.
Randomized phase II clinical trial to assess MUC1 specific immune response to L-BLP25 vaccine in addition to standard therapy in newly diagnosed high-risk prostate cancer.
Abstract No:TPS4701
Citation:
J Clin Oncol 30, 2012 (suppl; abstr TPS4701)
Author(s): Nishith K. Singh, Marijo Bilusic, Joseph W. Kim, Christopher Ryan Heery, Martin H. Falk, Bradford J Wood, Peter A. Pinto, William L. Dahut, Aradhana Kaushal, Anna Couvillon, Myrna Rauckhorst, Peter L. Choyke, Ismail B. Turkbey, Jane B. Trepel, Kwong Yok Tsang, Jeffrey Schlom, James L. Gulley, Ravi A. Madan; Laboratory of Tumor Immunology and Biology and Medical Oncology Branch, National Cancer Institute, Bethesda, MD; Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD; Medical Oncology Branch, National Cancer Institute, Bethesda, MD; Merck KGaA, Darmstadt, Germany; Department of Radiology and Imaging Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD; Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD; Radiation Oncology Branch, National Cancer Institute, Bethesda, MD; Molecular Imaging Program, CCR, NCI, NIH, Bethesda, MD; Center for Cancer Research, National Cancer Institute, Bethesda, MD; Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD; Laboratory of Tumor Immunology and Biology, Center for Cancer Research, Bethesda, MD
Abstract:
Background: In high-risk prostate cancer, radiation therapy (RT) + androgen deprivation therapy (ADT) improve survival. Nonetheless, 10-year disease specific mortality is about 25%. L-BLP25 is a cancer vaccine containing the BLP25 lipopeptide that targets MUC1 tumor antigen. It may enhance immune targeting of cells that express MUC1 (e.g. prostate cancer). In murine models, RT synergizes with vaccine-induced anti-cancer immunity (augments T-cell mediated cancer cytolysis, up-regulates cellular Fas and co-stimulatory/adhesion molecules). ADT augments T-cell trafficking to prostate. Immune response to combining the three (L-BLP25 + RT + ADT) is not known. The current trial intends to study this immune response to L-BLP25 + RT + ADT and compare it to RT+ADT alone. Using ELISPOT, endo-rectal MRI and serial prostate biopsies, this trial was designed to correlate systemic immune response with changes in tumor imaging and/or tumor microenvironment after treatment with L-BLP25. This trial may provide insight into immune response biomarkers that are most appropriate in this setting. Methods: A randomized (1:1), open-label, phase II trial of 42 pts is planned. Eligibility: Adult males with newly diagnosed high-risk prostate cancer (T3 or Gleason ≥ 8 or seminal vesicle involvement or N1 or PSA>20) and HLA-A2/A3 positivity (to allow for ELISPOT analysis). The vaccine arm will receive RT + 2-year ADT + L-BLP25. Standard arm will receive RT + 2-year ADT. L-BLP25 vaccine schedule: biweekly X 5 starting with neo-adjuvant ADT, then 6 weekly X 4 starting with RT. A single 300mg/m2 cyclophosphamide infusion (decreases suppressor T-cells) will be given 3 days before L-BLP25 to enhance immune response in the vaccine arm. The impact of L-BLP25 + RT+ADT on MUC-1-specific systemic immune response will be determined using interval peripheral blood ELISPOT assays. Endo-rectal coil MRI will be done before and after treatment to study prostate signal changes for correlative and predictive analysis. MRI-UltraSound guided lesion-targeted serial prostate biopsies will be obtained to assess immune response in tumor microenvironment. Two pts have been enrolled.
Abiraterone
A phase Ib/II study testing the safety and efficacy of combined inhibition of the AKT/PI3K and AR signaling pathways in castration-resistant prostate cancer: GDC-0068 or GDC-0980 with abiraterone acetate versus abiraterone acetate.
Abstract No:TPS2616
Citation:
J Clin Oncol 30, 2012 (suppl; abstr TPS2616)
Author(s): Roel Peter Funke, Jin Zhu, Raymond D. Meng, Yibing Yan, Luna C. Musib, Craig Charles Talluto, Premal H. Patel; Genentech, South San Francisco, CA
Abstract:
Background: Loss of PTEN, leading to activation of the AKT/PI3K pathway is frequent and associated with poor prognosis in prostate cancer. In addition, AR and AKT/PI3K cross-regulate by reciprocal feedback and combined inhibition of both pathways resulted in improved preclinical efficacy. This study is designed to evaluate the effect of combined inhibition of AR pathway (with abiraterone) and AKT/PI3K pathway (with either GDC-0068 or GDC-0980). GDC-0068 is a potent, selective ATP-competitive inhibitor of AKT1, 2, and 3. Preclinical studies showed that cell and tumor models with PTEN loss are more likely to be sensitive to GDC-0068. GDC-0068 was generally well tolerated in phase I and a MTD of 600 mg daily was identified. GDC-0980 is a potent pan-inhibitor of Class I PI3K and inhibits wild-type and mutated p110α isoforms, as well as mTOR kinase. The recommended phase II dose (RP2D) for single-agent GDC-0980 is 40 mg daily. Methods: This study will enroll CRPC patients previously treated with docetaxel. In phase Ib, the RP2D will be determined separately for GDC-0068 and GDC-0980 in combination with abiraterone 1000 mg qd and prednisone 5mg bid. In phase II, patients will be randomized 1:1:1 to receive GDC-0068 + abiraterone, GDC-0980 + abiraterone, or placebo + abiraterone. The primary endpoint of phase II is PFS measured by PCWG2 in all patients and in patients with PTEN loss. Secondary endpoints include OS, PSA response rate, ORR, safety, Pharmacokinetics and biomarker analyses. The effect of each treatment on the number of circulating tumor cells will be assessed. Primary and secondary analyses will include all randomized patients and will be conducted according to assigned treatment arm. Kaplan-Meier methodology will be used to estimate median PFS for each arm. Up to 24 patients are planned to be enrolled in phase Ib; 240 patients (80 per arm) are planned for phase II. This study is open for accrual; to date 2 patients have been enrolled in phase Ib.
Cytoreduction and androgen signaling modulation by abiraterone acetate (AA) plus leuprolide acetate (LHRHa) versus LHRHa in localized high-risk prostate cancer (PCa): Preliminary results of a randomized preoperative study.
Abstract No:4556
Citation:
J Clin Oncol 30, 2012 (suppl; abstr 4556)
Author(s): Eleni Efstathiou, John W. Davis, Patricia Troncoso, Mark Anton Titus, Anh Hoang, Sijin Wen, Amado J. Zurita, Namphuong Tran, Arturo Molina, Christopher Logothetis; University of Athens, Athens, Greece; University of Texas M. D. Anderson Cancer Center, Houston, TX; University of Texas M. D. Anderson Cancer Center, Houston, TX; Roswell Park Cancer Institute, Buffalo, NY; Janssen Research & Development, Los Angeles, CA