Search

9554 Background: IMM-101 is a suspension of heat-killed whole cell Mycobacterium obuense (NCTC 13365), which enhances the innate immune response and dendritic cell maturation. In animal models, it increases antigen specific responses and number of CD8+ CTL and CD4 + Th1 cells. The clinical studies with IMM-101 have shown promising efficacy signals in pancreatic cancer when combined with gemcitabine and in melanoma as adjunctive or single agent. Methods: IMM-101-015 is an open-label Phase 2a study to investigate the safety and efficacy of IMM-101 in combination with checkpoint inhibitors (CPIs) in patients (pts) with advanced melanoma who were either treatment-naive (cohort A), or whose disease had progressed during PD-1 blockade (cohort B). Pts with evaluable lesions, adequate performance status and organ function were eligible. Pts received 1.0 mg of IMM-101 every 2 weeks for the first 3 doses followed by a rest period of 4 weeks, then every 2 weeks for the next 3 doses, and thereafter every 4 weeks. Nivolumab was given every 2 or 4 weeks (dependent on Investigator choice). Pts in cohort B had the option to change to ipilimumab and IMM-101 if their disease continued to progress. Biopsies and blood samples were obtained at baseline and during treatment for assessment of tumor biomarkers and immune correlatives. The primary objectives of the study were to evaluate the overall response rate (ORR) after a maximum of 18 months of treatment by RECIST 1.1 and to assess the safety and tolerability of the combination of IMM-101 + CPIs. Results: Sixteen pts (11 Cohort A and 5 Cohort B) were treated between October 2018 and May 2021. The median age was 68.5 yrs (range 36-92) and 11 (69%) were male. The ECOG ps was 0 in 9 (56%) and 1 in 7 (44%) pts. Four (25%) had unresectable stage III melanoma and 12 (75%) stage IV. In Cohort A (3 stage III, 5 stage IV M1b and 3 M1c) 3 pts (27%) had an elevated baseline LDH, 6 (55%) a positive PD-L1 status and 3 (27%) a BRAF mutation. Pts in cohort A were on study for a median time of 8.5 months (range 1.5 - 19.1) and those in cohort B for 3.0 months (range 1.5 - 7.4). All pts were evaluated for response. The ORR was 73% (95% CI 39.03, 93.98) in cohort A whereas all pts in cohort B reported progressive disease. With respect to cohort A, 2 (18%) pts had CR, 6 (55%) PR and 1 (9%) SD. The median progression-free survival time was 10.2 months (95% CI 2.50, NE) with 41% of the pts progression-free at 18 months. The most frequent treatment emergent adverse events (TEAEs) were injection site reaction (63%), pruritus (44%), fatigue (38%), skin rash (25%), hypothyroidism (25%) and diarrhoea (19%). There were no grade 4 TEAEs. Grade 3 TEAEs occured in 10 patients (63%), mostly skin toxicity (19%) and lab abnormalities (13%). Conclusions: IMM-101 in combination with nivolumab is safe and shows encouraging antitumor activity in treatment-naive patients with advanced melanoma. Clinical trial information: NCT03711188.

9523 Background: ImmTAC molecules are unique TCR–anti-CD3 bispecifics that redirect T cells against intracellular antigens. IMCgp100, an ImmTAC targeting melanocyte-expressed gp100 antigen, has demonstrated monotherapy activity in advanced melanoma and can cause rash and cytokine-mediated AEs, hypothesized to be on-target (gp100) or effector (CD3) mediated. A preclinical MoA for T cell bispecifics suggests chemokine CXCL10 redirection of CXCR3+ T cells from blood into antigen-positive tissues; this has not been clinically validated. Methods: 84 HLA-A2+ pts with advanced melanoma (n = 61 cutaneous [CM], n = 19 uveal [UM], n = 4 other) received IMCgp100 (NCT01211262). Serum (n = 40) and PBMC (n = 22) samples were taken pre- and post-infusion to analyze changes in cytokines and circulating T cells. Pre- (n = 16) and post-treatment (n = 11) tumor biopsies were analyzed by IHC for CD3, PD-L1 and gp100 expression; tumor RNA (n = 12) was analyzed for gene expression. Results: IMCgp100 induced a transient increase in IFNg-inducible cytokines, most prominently CXCL10. A greater increase in serum CXCL10 was associated with longer OS (p = 0.0002), tumor shrinkage (p = 0.003), and greater transient reduction in peripheral CXCR3+CD8+ T cells (p = 0.001). Reduction in CXCR3+ CD8+ T cells also trended with longer OS (p = 0.02), and tumor shrinkage (p = 0.03). 3/16 pre-treatment biopsies had < 1% gp100 expression (all progressive disease). 8/11 biopsies post-IMCgp100 had increased CD3+ T cells compared with matched pre-treatment samples (associated with baseline gp100 but not PD-L1 expression). Based on tumor biopsy gene expression analysis, IMCgp100 increased T cell markers, IFNg-inducible and cytotoxicity-related genes. Conclusions: The association of clinical benefit with increased serum CXCL10 and decreased peripheral CXCR3+ T cells supports the MoA of IMCgp100-induced T cell redirection and activation. Tumor biopsy results support IMCgp100 redirection of T cells to antigen-positive tumor. A Phase II trial in CM (NCT02535078), a Phase I/II trial in UM (NCT02570308), and a Pivotal RCT in UM (NCT03070392) are ongoing. Clinical trial information: NCT01211262.

3018 Background: Since publication of the registration trial in 2010 (Hodi et al, NEJM 2010;363:711-23), real world use of ipilimumab (Ipi) in previously treated advanced melanoma patients has extended beyond the specific trial entry criteria of ECOG PS 0-1. We undertook a review of UK patients (pts) treated in the international EAP prior to European licensing of Ipi in August 2011, to compare real world survival outcomes. Methods: UK clinicians registered in the EAP provided anonymised data using pre-specified variable fields for all pts. The EAP stipulated pts should have previously treated, unresectable stage III or IV metastatic melanoma and receive Ipi 3 mg/kg, 3 weekly IV, for up to 4 cycles. Response using RECIST criteria was assessed 12 weekly. Grade ≥3 adverse events (AEs) using CTCAE v3.0 were collected. Results: To date, information on 162 pts has been received from 16 UK sites. Primary sites were: 78% cutaneous, 4% ocular, 1% mucosal, 17% unknown. 78% pts had M1c disease, 14% had brain metastases. No prior therapies ranged from 0-4, 72% pts received 1 prior therapy. Median age was 60 years, men>women (1.6:1). ECOG PS was: 38% 0, 47% 1, 14% 2, 1% 3. BRAF status was known in 38% cases and WT in 75% of these. 19% pts were on steroids at baseline. No cycles delivered was 4 in 52%, 3 in 13%, 2 in 16%, 1 in 17% pts. Most frequent reason for stopping early was clinical evidence of disease progression (71%), death (16%) or unacceptable AE (12%). 32% pts experienced a grade ≥3 AE, the most common being diarrhoea (13%) and fatigue (8%). Complete and partial responses were reported in 1% and 21% of treated pts. At median follow-up of 17 months, median progression free survival and overall survival (OS) were 2.8 and 5.7 months, 1 year OS was 30%. Comparing outcomes of various pt subgroups, the strongest prognostic factor for OS was ECOG PS at the start of treatment (p

2586 Background: Targeting poly (ADP-ribose) polymerase (PARP), an enzyme involved in DNA damage repair, may increase efficacy of DNA-damaging agents. This study evaluated the tolerability of oral rucaparib, a potent and selective PARP1/2 inhibitor, in combination with carboplatin (CP). Methods: Patients (pts) aged ≥18 with advanced solid tumors were included. Pts received lead-in doses of IV and oral rucaparib on Days -10 and -5, respectively, followed by CP on Day 1 and oral rucaparib on Days 1-14 q21 days. Treatment continued until disease progression. Pts with benefit could continue on rucaparib monotherapy once CP dosing was completed. Dose escalation was based on toxicities observed in Cycle 1 in cohorts of n=3-6. PK was assessed during Cycle 1. Results: 23 pts (median age 62 yrs [range 20 – 76]; 16 female; 9 ECOG PS=0; 6 ovarian/peritoneal cancer (OC), 5 breast cancer (BC), 2 NSCLC, 10 other tumor) were enrolled. Rucaparib doses of 80, 120, 180, 240, and 360 mg were administered with AUC3 CP, followed by 360 mg rucaparib with AUC4 CP, and currently with AUC5 CP. No DLTs have been reported. Median treatment cycles is 3 (range 1 – 15+). Treatment-related adverse events in ≥4 pts, all grades, include anemia (n=10), fatigue (n=9), nausea (n=7), thrombocytopenia (n=6), constipation (n=5), lethargy (n=5), neutropenia (n=5), and anorexia (n=4). One pt (OC, BRCAwt, AUC3 CP/180 mg rucaparib) had a PR of 5.1 mo duration. Two patients (both with OC; 1 BRCAunk, 1BRCAwt) discontinued CP (after 4 & 8 cycles) and continued on rucaparib monotherapy (additional 5 and 7+ cycles, respectively). An additional 4 pts (all BRCAunk) had stable disease (SD) >12 wks. Overall disease control rate (CR+PR+SD>12 wks) in OC pts across all dose levels was 50% (3/6). Dose-proportional increase in rucaparib exposure was observed with steady state achieved by Day 14 and mean t1/2of 15 h. Oral bioavailability was 38% and dose-independent. Rucaparib exposure was not changed by CP co-administration. Conclusions: The combination of oral rucaparib and CP is well tolerated and exhibits activity at clinically relevant doses of each agent. Further studies in platinum-sensitive and homologous recombination repair deficient populations are warranted. Clinical trial information: NCT01009190.

9068 Background: Inhibitors of mutant BRAF have transformed the treatment of melanoma for the 40% of patients whose tumors harbor V600 mutations. ERK1/2 is constitutively active in melanoma cells regardless of mutation status, and plays key roles in cell cycle entry, invasion, angiogenesis and in resistance to apoptosis. Selumetinib is a highly selective allosteric inhibitor of MEK1/2, suppressing pERK levels in melanoma independent of BRAF and NRAS mutation status. In melanoma cells, docetaxel induces mitochondrial dependent apoptosis by activation of Bax. Activation of ERK1/2 results in degradation of the BH3-only protein Bim and phosphorylation of Bad, inhibiting apoptosis. Selumetinib and docetaxel have demonstrated synergy in a variety of xenograft models, including melanoma. Methods: DOC-MEK (NCT01256359) is a randomised, double-blind, placebo-controlled multi-centre study in patients with wild-type BRAF advanced melanoma. Patients were randomised (1:1) to docetaxel with placebo or selumetinib, with stratification for M stage and performance status. Docetaxel was administered intravenously every 3 weeks at a dose of 75mg/m2 for a maximum 6 cycles. Placebo or selumetinib 75mg was given orally twice per day until disease progression or unacceptable toxicity. Results: Between October 2010 and April 2012 eighty three patients were randomised at 18 sites from 257 patients screened. Progression free survival (PFS) favored combination therapy (HR 0.753, p=0.13), as did response rate (32 vs 14%, p=0.059) and 6 month PFS (40 vs 26%, p=0.19). Patients on docetaxel with selumetinib experienced more rash, diarrhea, febrile neutropenia and edema, but less neuropathy. Overall survival data and outcomes according to tumor NRAS mutation status will be presented. Conclusions: Although PFS and response rates favored docetaxel with selumetinib further interest in the regimen will be dependent on overall survival outcomes and/or the identification of a sub-population that benefit most from this approach. Clinical trial information: NCT01256359.

3051 Background: We previously reported the comparative bioavailability of the olaparib tablet (TAB) up to 200 mg BID, with the initial capsule formulation; gmean AUC0–T following 200 mg BID TAB was ~20% lower than 400 mg BID capsule (CAP; Molife et al ASCO 2010). Olaparib 200 mg BID TAB had an acceptable tolerability profile suggesting further dose escalation might be justified. Methods: Study NCT00777582 was amended to include a dose-escalation phase, to define the maximum tolerated dose (MTD) and safety profile of the TAB, and 2 expansion phases to compare safety and efficacy of TAB doses vs 400 mg BID CAP. Expansion phase data are reported separately. Here, we report preliminary data from the dose-escalation phase where patients (pts) with advanced solid tumors, ECOG PS 0–2 and adequate organ function were assigned to treatment with increasing olaparib BID TAB doses in 28-day continuous dosing cycles. Pharmacokinetic (PK) sampling was performed on days 1, 8, 15, 29, 57. Results: 30 pts (M:F, 3:27; median age 54 yrs [range 19–70]) were enrolled in the dose-escalation phase and received treatment at 5 dose levels: 250, 300, 350, 400 and 450 mg (each dose level, n=6). Overall, the most common AEs were nausea (80%), fatigue (73%) and diarrhea (36%). The majority of AEs were mild to moderate (CTC grade [G] 1/2). Hematologic toxicity in terms of, mostly mild, anemia, neutropenia and thrombocytopenia, appeared to increase at doses of 300 mg BID or higher. Two pts had dose-limiting toxicities at 450 mg (G3 thrombocytopenia and G3 anemia); the TAB MTD was 400 mg BID. Exposure increased proportionally with increasing dose: mean exposure after 400 mg BID was double that following the previously reported 200 mg BID dose. Following 300 and 400 mg doses, gmean Cmax ss, AUC0–T and Cmin ss matched or exceeded the 400 mg BID CAP dose. Conclusions: The MTD of olaparib TAB was 400 mg BID. Based on PK analysis, the 300 and 400 mg BID doses were selected for evaluation in the MTD expansion phase to further define safety and preliminary efficacy.