Shubham Pant

A phase I dose escalation study of oral c-MET inhibitor tivantinib (ARQ 197) in combination with gemcitabine in patients with solid tumors

BACKGROUNDnTivantinib (ARQ 197) is an orally available, non-adenosine triphosphate competitive, selective c-MET inhibitor. The primary objective of this study was to evaluate the safety, tolerability and to establish the recommended phase II dose (RP2D) of tivantinib and gemcitabine combination.nnnPATIENTS AND METHODSnPatients with advanced or metastatic solid tumors were treated with escalating doses of tivantinib (120-360 mg capsules) in combination with gemcitabine (1000 mg/m(2) weekly for 3 of 4 weeks). Different schedules of administration were tested and modified based on emerging preclinical data. Tivantinib was given continuously, twice a day (b.i.d.) for 2, 3 or 4 weeks of a 28-day cycle or on a 5-day on, 2-day off schedule (the day before and day of gemcitabine administration).nnnRESULTSnTwenty-nine patients were treated with gemcitabine and escalating doses of tivantinib: 120 mg b.i.d. (n = 4), 240 mg b.i.d. (n = 6) and 360 mg b.i.d. (n = 19). No dose-limiting toxicities were observed in escalation. The RP2D was 360 mg b.i.d. daily, and 45 additional patients were enrolled in the expansion cohort. Grade ≥3 treatment-related toxicities were observed in 54 of 74 (73%) patients with the most common being neutropenia (43%), anemia (30%), thrombocytopenia (28%) and fatigue (15%). There was one treatment-related death due to neutropenia. Administration of gemcitabine did not affect tivantinib concentration. Fifty-six patients were assessable for response. Eleven (20%) patients achieved a partial response and 26 (46%) had stable disease (SD), including 15 (27%) who achieved SD for over 4 months. Ten of 37 patients with clinical benefit had prior exposure to gemcitabine.nnnCONCLUSIONnThe combination of tivantinib at its monotherapy dose and standard dose gemcitabine was safe and tolerable. Early signs of antitumor activity may warrant further development of this combination in nonsmall-cell lung cancer, ovarian, pancreatic and cholangiocarcinoma.nnnCLINICALTRIALSGOV IDENTIFIERnNCT00874042.BACKGROUNDnTivantinib (ARQ 197) is an orally available, non-adenosine triphosphate competitive, selective c-MET inhibitor. The primary objective of this study was to evaluate the safety, tolerability and to establish the recommended phase II dose (RP2D) of tivantinib and gemcitabine combination.nnnPATIENTS AND METHODSnPatients with advanced or metastatic solid tumors were treated with escalating doses of tivantinib (120-360mg capsules) in combination with gemcitabine (1000mg/m2 weekly for 3 of 4 weeks). Different schedules of administration were tested and modified based on emerging preclinical data. Tivantinib was given continuously, twice a day (b.i.d.) for 2, 3 or 4 weeks of a 28-day cycle or on a 5-day on, 2-day off schedule (the day before and day of gemcitabine administration).nnnRESULTSnTwenty-nine patients were treated with gemcitabine and escalating doses of tivantinib: 120mg b.i.d. (n = 4), 240mg b.i.d. (n = 6) and 360mg b.i.d. (n = 19). No dose-limiting toxicities were observed in escalation. The RP2D was 360mg b.i.d. daily, and 45 additional patients were enrolled in the expansion cohort. Grade ≥3 treatment-related toxicities were observed in 54 of 74 (73%) patients with the most common being neutropenia (43%), anemia (30%), thrombocytopenia (28%) and fatigue (15%). There was one treatment-related death due to neutropenia. Administration of gemcitabine did not affect tivantinib concentration. Fifty-six patients were assessable for response. Eleven (20%) patients achieved a partial response and 26 (46%) had stable disease (SD), including 15 (27%) who achieved SD for over 4 months. Ten of 37 patients with clinical benefit had prior exposure to gemcitabine.nnnCONCLUSIONnThe combination of tivantinib at its monotherapy dose and standard dose gemcitabine was safe and tolerable. Early signs of antitumor activity may warrant further development of this combination in nonsmall-cell lung cancer, ovarian, pancreatic and cholangiocarcinoma. CLINICALTRIALS.nnnGOV IDENTIFIERnNCT00874042.

Genetic landscape of gallbladder cancer: Global overview

Gallbladder cancer (GBC) is a rare malignancy of biliary tract cancer (BTC), characterized by late presentation and poor prognosis. It exhibits wide geographical as well as ethnical variations. So, diverse epidemiology along with etiological factors have been discussed in the current article. Present review unravels the germ line polymorphisms contributing to GBC susceptibility through candidate gene approach and GWAS. GBC is enriched with multiple mutations consisting of both passenger and driver mutations. The identification of the hotspot driver mutations which are involved in the etiopathogenesis of this cancer is necessary, before targeted therapies could be implemented clinically. Thus, this review sheds lights on both traditional low throughput methods along with high throughput NGS used to determine somatic mutations in cancer. With the advent of GWAS and high throughput sequencing methods, it is possible to comprehend the mutational landscape of this enigmatic disease. This article is the first one to provide insights into the genetic heterogeneity of GBC along with somatic mutational data from Catalogue of Somatic Mutations in Cancer (COSMIC) database. In addition, management of tumor heterogeneity as a therapeutic challenge has been discussed. Future goals involve liquid biopsy based research for better clinical management of the disease. Therefore, research efforts involving discovery of non- invasive markers for early stage cancer detection along with novel therapies should be directed.

Clinical update on K-Ras targeted therapy in gastrointestinal cancers

KRAS mutations are common in pancreatic and colorectal cancers and are associated with lack of response to anti-epidermal growth factor receptor therapy. Ras is an established therapeutic target that has long eluded efforts to develop specific inhibitors, while targeting downstream signaling pathways has proven largely ineffective, highlighting a need for rational combination strategies to overcome resistance. Recently, renewed interest in directly targeting Ras has led to the development of several small-molecule inhibitors that bind directly to K-Ras or its effector proteins, downregulation of K-Ras expression using therapeutic antisense oligonucleotides or siRNAs, and targeting scaffold proteins such as kinase suppressor of Ras. Indirect approaches to inhibiting K-Ras include combining inhibitors of the mitogen-activated protein kinase pathway with novel targeted agents. Immunotherapy in early studies has also shown clinical promise. This review summarizes the current evidence for each of these approaches.

Abstract PR08: Antitumor activity and immune correlates of PEGylated human IL-10 (AM0010) alone or in combination with anti-PD-1

Background: The success of and the durability of immune therapy of cancer is thought to depend on the activation and expansion of tumor reactive and infiltrating CD8+ T cells. The response to immune checkpoint blockade, depends on a pre-existing, CD8 T cell-rich tumor microenvironment. IL-10 stimulates the antigen mediated cytotoxicity, survival and proliferation of intra-tumoral CD8+ T cells and simultaneously dampens chronic inflammation. T cell receptor mediated activation of CD8 T cells induces the expression of IL-10 receptors on these cells. IL-10 activates with STAT3 an essential survival and proliferation signal in antigen activated CD8 T cells. This also provides a mechanistic rationale for combining AM0010 and anti-PD1 in the clinic. To evaluate the clinical activity, tolerability and anti-tumor activity of AM0010 alone or in combination with chemotherapy or immune checkpoint inhibitors a multi-basket phase 1 study was conducted. Additional disease specific expansion cohorts for the combination of AM0010 with FOLFOX in pancreatic cancer or with nivolumab in RCC or NSCLC are currently evaluated Results: Tolerability and anti-tumor activity of AM0010 alone or in combination with chemotherapy or immune checkpoint inhibitors was established in this multi-basket phase 1 study. In monotherapy, objective responses were observed in pts with uveal melanoma, cutaneous T cell lymphoma and in 4 of 15 pts with RCC. Patients with advanced melanoma, RCC or NSCLC were also treated with AM0010 (daily SC) in combination with anti-PD-1 immune checkpoint blockade. Tumor responses were monitored following irRC. Immune responses were measured by analysis of serum cytokines, activation of blood derived T cells, peripheral T cell clonality and immunohistochemistry of tumor infiltrating CD8 T cells. In 19 pts, AMO010 10 μg/kg (n = 13) or 20 μg/kg (n = 6) in combination with anti-PD1 - pembrolizumab (2mg/kg) was well tolerated (observation period 10-15 months). Immune related TrAE occured in the frequency and severity as expected from pembrolizumab montherapy. The combination of AM0010 with pembrolizumab achieved objective responses (PR/CR) in 4 of 8 RCC pts, 2 of 5 NSCLC pts and 2 of 6 melanoma pts. 2 additional melanoma pts had tumor increase followed by decrease (pseudoprogression). Independent of the combination with either chemotherapy or anti-PD-1, AM0010 increased Th1 cytokines (IL-18, IFNγ, IL-7) in a dose dependent fashion. FasL and lymphotoxin beta - products of cytotoxic T cells - were also increased in the serum of AM0010 treated patients. In contrast, mediators of chronic inflammation, such as IL-23 and IL-17 and the immune suppressive cytokine TGFbeta were reduced in the serum of patients. AM0010 increased the number and proliferation of PD1+ activated CD8 T cells while decreasing the proliferation of FoxP3+ Tregs and TGFβ in the blood. AM0010 induced de-novo oligoclonal expansion of T cell clones in the blood of patients without affecting total lymphocyte counts. This clonal expansion appeared enhanced and accelerated in patients treated with a AM0010 anti PD-1 combination, but was also seen in patients which received a AM0010 - chemotherapy combination. AM0010 also increased the number of tumor infiltrating Phospho-STAT3+ CD8 T cells in tumors and the number of Granzyme+ PD1+ CD8+ T cells in tumor biopsies of treated patients. Conclusion: AM0010 alone or in combination with anti-PD1 is well-tolerated. The clinical activity and the observed CD8 T cell activation encourages the phase 2/3 studies of AM0010 in combination with anti-PD1 planned for later in 2016. Trial registration: www.clinicaltrials.govNCT02009449. Citation Format: Aung Naing, Jeffrey R. Infante, Kyriakos P. Papadopoulos, Deborah J. Wong, Karen A. Autio, Gerald S. Falchook, Manish Patel, Shubham Pant, Amita Patnaik, Melinda Whiteside, Johanna C. Bendell, John Mumm, Ivan H. Chan, Gail L. Brown, Peter VanVlasselaer, J. R. Hecht, David S. Hong, Nizar M. Tannir, Martin Oft. Antitumor activity and immune correlates of PEGylated human IL-10 (AM0010) alone or in combination with anti-PD-1 [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr PR08.