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R.E. Sanborn
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P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.01-075 - Phase III, Randomized, Double-Blind Trial of Bavituximab Plus Docetaxel in Previously Treated Stage IIIb/IV Non-Squamous NSCLC (SUNRISE) (ID 1581)
09:30 - 09:30 | Author(s): R.E. Sanborn
- Abstract
Background:
Exposed phosphatidylserine (PS) in the tumor microenvironment is highly immunosuppressive. PS binding to PS receptors on myeloid derived suppressor cells (MDSC) and M2 macrophages leads to production of anti-inflammatory cytokines such as TGF-β and IL-10. Bavituximab, a first-in-class PS-targeting monoclonal antibody, counters these effects, resulting in production of pro-inflammatory cytokines such as TNF-α and IL-12, maturation of dendritic cells and induction of tumor specific cytotoxic T lymphocyte (CTL) immunity. Docetaxel has also been shown to suppress MDSCs while increasing tumor antigens and T-cell mediated cytotoxicity, thereby enhancing bavituximab’s immunomodulatory effects. In a prior double-blind Phase II trial in 2nd line non-squamous non-small cell lung cancer, bavituximab 3 mg/kg plus docetaxel was well-tolerated and demonstrated 60% improvement (11.7 vs 7.3 month) in median overall survival (OS) compared to control.
Methods:
SUNRISE is a Phase III, double-blind trial where patients with previously treated Stage IIIb/IV non-squamous, non-small cell lung cancer are randomized in a 1:1 ratio to receive up to six 21-day cycles of docetaxel in combination with either weekly 3 mg/kg bavituximab or placebo, followed by maintenance with weekly bavituximab or placebo until progression or toxicity. Patients will be stratified by region (North America, Europe, or Rest of World), disease stage (IIIb or IV), and previous maintenance/targeted therapy (yes or no). This trial was initiated in December 2013 and accrual of 582 patients across 160+ sites in 14 countries is planned over 24 months. The primary endpoint is OS and two interim analyses are planned. Secondary endpoints include progression-free survival (PFS), overall response rate (ORR) and safety. Radiographic tumor response is centrally assessed every two cycles during combination therapy and every nine weeks during maintenance. Exploratory analysis will include the assessment of changes in circulating immune cells and cytokines to better understand the immunotherapeutic mechanism.
Results:
Trial in progress
Conclusion:
Trial in progress
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P2.07 - Poster Session/ Small Cell Lung Cancer (ID 222)
- Event: WCLC 2015
- Type: Poster
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.07-008 - CTC 11-001: PhI Study of Carfilzomib (C) + Irinotecan (I) in Relapsed, Irinotecan Sensitive Solid Tumors (ID 241)
09:30 - 09:30 | Author(s): R.E. Sanborn
- Abstract
Background:
Inactivation of proteasome function allows for increased apoptosis and the potential for enhanced antitumor effect by chemotherapy. Carfilzomib (C) and Irinotecan (I) potentially synergize by increasing camptothecin-induced apoptosis and interfering with topoisomerase-I degradation, preventing DNA damage repair. This report describes the initial phase I study of C + I in adults with relapsed, irinotecan-sensitive cancers including small cell lung cancer (SCLC).
Methods:
The primary endpoint was determination of the MTD of 28-day cycle 1 of I (D1,8,15) and C (D1,2,8,9,15,16) using a standard 3+3 Ph1 design. Toxicity and response were evaluated using NCI CTCAE (v4) and RECIST (v1.1). Pharmacodynamics endpoints (proteasome activity, topo-1 expression, and gamma-H2AX protein expression in PBMC) were assessed on C1D1 and C1D2.
Results:
16 patients were enrolled at 3 dose levels of C (mg/m2/d) using stepped-up dosing: 20 mg given C1D1 & C1D2 then increased to the dose indicated: 20/27 (N=4), 20/36 (N=9), 20/45 (N=3) and I dosed at 125 mg/m2d. Median age: 64 (range 56-78), 8 M/8F. Tumor types included: SCLC (N=13), non-small cell lung cancer (NSCLC) (N=2) and ovarian (N=1). 6 subjects completed 2 or more cycles of therapy, 4 subjects were not evaluable for dose-limiting toxicity (DLT) secondary to rapid progressive disease (PD) or withdrawal and were replaced. 2 DLTs were observed in cohort 3, Grade (Gr)4 thrombocytopenia lasting ≥ 7 days and Gr3 diarrhea lasting ≥ 7 days) and 1 DLT in cohort 2 (Gr3 diarrhea lasting > 7 days). Serious adverse events (SAEs) by dose level: 20/27: Gr3 Dysphagia and recurrent laryngeal nerve palsy, (unrelated); Gr3 peripheral motor neuropathy and Gr3 urinary incontinence, (unrelated); 20/36: Gr3 fatigue, multiple occurrences; Gr3 diarrhea with dehydration; Gr3 cholelithiasis with dehydration (unrelated); 20/45: Gr3 dehydration, Gr3 anemia, Gr2 anemia and Gr3 acute on chronic kidney disease. Common Gr3/4 AEs were: fatigue (19%), thrombocytopenia (19%), diarrhea (13%), anemia (6%), neutropenia (6%), and leukopenia (6%). One patient (25%), five patients (55%), and two patients (67%) experienced Gr3/4 AEs in cohorts 1, 2, and 3, respectively. The maximum tolerated dose was exceeded at 20/45. Antitumor activity (stable disease or better) was observed in 3 SCLC subjects to date, with updated follow-up to be reported.
Conclusion:
C and I is a well-tolerated combination with anti-tumor activity in heavily pretreated patients. The recommended phase 2 dose of Carfilzomib is 20/36 mg/m2/d in combination with Irinotecan 125 mg/m2/d. A phase 2 study in SCLC is ongoing through the Lung Cancer Research Team (LCRT). This study was supported by Onyx Pharmaceuticals, a subsidiary of Amgen Corporation. Clinical trial information: NCT01941316.
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P3.03 - Poster Session/ Treatment of Locoregional Disease – NSCLC (ID 214)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.03-016 - Randomized ph II Trial of Cyclophosphamide with Allogeneic DPV-001 Cancer Vaccine Alone or with Adjuvant for Curatively-Treated Stage III NSCLC (ID 3028)
09:30 - 09:30 | Author(s): R.E. Sanborn
- Abstract
Background:
Tumor-derived autophagosomes (DRibbles) are a novel dendritic cell-targeted cancer immunotherapy that preclinically provides cross-protection against related tumors and efficacy against established tumors. We hypothesize DRibbles’ efficacy is due to presentation of stabilized tumor-derived short-lived proteins (SLiPs) and defective ribosomal products (DRiPs) normally not processed or presented by antigen presenting cells (APCs). SLiPs and DRiPs provide a potential pool of tumor antigen to which the host may not be not tolerant. This DRibble DPV-001 vaccine packages several hundred putative cancer antigens, including 13 antigens from the NCI list of priority antigens and agonist activity for TLR 2, 3, 4, 7 and 9 into stable double membrane microvesicles which have surface molecules targeting DRibbles to CLEC9A+ APCs (the most effective APC at cross-priming immunity). DPV-001 contains an average of 176 proteins from genes overexpressed in NSCLC patient tumors. Many of these putative cancer antigens have single amino acid variants that may serve as mimetopes, or altered peptide ligands, and thereby increase immunogenicity.
Methods:
Pts are eligible after completion of standard curative-intent therapy for stage III NSCLC. Pts receive induction cyclophosphamide, then 7 DPV-001 vaccines at 3-week intervals. The first vaccine is given intranodally; subsequent vaccines intradermally. Pts are randomized to receive DRibble alone, or with adjuvant imiquimod or GM-CSF. Peripheral blood mononuclear cells and serum are collected at baseline and at each vaccination. Serum from baseline and week 12 is analyzed for antibody response to >9000 human proteins (ProtoArray). When available, multispectral Immunoprofiling is performed on tumor to evaluate pre-existing immunity and Human Exome Capture and Next Generation Sequencing is done on tumor (100x coverage) and matched normal tissue. Tumor somatic mutations are compared to DPV-001 to identify shared non-synonymous single nucleotide variations (nsSNVs) with the vaccine, including mutations with potential increased immunogenicity. Pts will be analyzed comparatively for strong antibody responses (>15 fold increase in titer). 11 pts will be randomized to each arm, with 15 more enrolled on the arm with greatest number of strong antibody response. 8 pts have been enrolled, and accrual is ongoing.
Results:
Not applicable
Conclusion:
Not applicable
