Jonathan Greenberg

Phase 2, multicenter, open-label study of tigatuzumab (CS-1008), a humanized monoclonal antibody targeting death receptor 5, in combination with gemcitabine in chemotherapy-naive patients with unresectable or metastatic pancreatic cancer.

Tigatuzumab is the humanized version of the agonistic murine monoclonal antibody TRA‐8 that binds to the death receptor 5 and induces apoptosis of human cancer cell lines via the caspase cascade. The combination of tigatuzumab and gemcitabine inhibits tumor growth in murine pancreatic xenografts. This phase 2 trial evaluated the efficacy of tigatuzumab combined with gemcitabine in 62 chemotherapy‐naive patients with histologically or cytologically confirmed unresectable or metastatic pancreatic cancer. Patients received intravenous tigatuzumab (8 mg/kg loading dose followed by 3 mg/kg weekly) and gemcitabine (1000 mg/m2 once weekly for 3 weeks followed by 1 week of rest) until progressive disease (PD) or unacceptable toxicity occurred. The primary end point was progression‐free survival (PFS) at 16 weeks. Secondary end points included objective response rate (ORR) (complete responses plus partial responses), duration of response, and overall survival (OS). Safety of the combination was also evaluated. Mean duration of treatment was 18.48 weeks for tigatuzumab and 17.73 weeks for gemcitabine. The PFS rate at 16 weeks was 52.5% (95% confidence interval [CI], 39.3–64.1%). The ORR was 13.1%; 28 (45.9%) patients had stable disease and 14 (23%) patients had PD. Median PFS was 3.9 months (95% CI, 2.2–5.4 months). Median OS was 8.2 months (95% CI, 5.1–9.6 months). The most common adverse events related to tigatuzumab were nausea (35.5%), fatigue (32.3%), and peripheral edema (19.4%). Tigatuzumab combined with gemcitabine was well tolerated and may be clinically active for the treatment of chemotherapy‐naive patients with unresectable or metastatic pancreatic cancer.

Safety and efficacy of tigatuzumab plus sorafenib as first-line therapy in subjects with advanced hepatocellular carcinoma: A phase 2 randomized study

BACKGROUND & AIMS Tigatuzumab is a humanized monoclonal antibody that acts as a death receptor-5 agonist and exerts tumour necrosis factor-related apoptosis-inducing ligand-like activity. In this phase II study, safety and tolerability of the combination of tigatuzumab and sorafenib was evaluated in patients with advanced hepatocellular carcinoma. METHODS Adults with advanced hepatocellular carcinoma, measurable disease, and an Eastern Cooperative Oncology Group performance score⩽1 were enrolled. Eligible subjects were randomly assigned 1:1:1 to tigatuzumab (6 mg/kg loading, 2 mg/kg/week maintenance) plus sorafenib 400 mg twice daily; tigatuzumab (6 mg/kg loading, 6 mg/kg/week maintenance) plus sorafenib 400 mg twice daily; or sorafenib 400 mg twice daily. The primary end point was time to progression. Secondary end points included overall survival and safety. RESULTS 163 subjects were randomized to treatment. Median time to progression was 3.0 months in the tigatuzumab 6/2 mg/kg combination group (p=0.988 vs. sorafenib), 3.9 months in the tigatuzumab 6/6 mg/kg combination group (p=0.586 vs. sorafenib), and 2.8 months in the sorafenib alone group. Median overall survival was 12.2 months in the tigatuzumab 6/6 mg/kg combination group (p=0.659 vs. sorafenib), vs. 8.2 months in both other treatment groups (p=0.303, tigatuzumab 6/2 mg/kg combination vs. sorafenib). The most common treatment-emergent adverse events were palmar-plantar erythrodysesthesia syndrome, diarrhea, and decreased appetite. CONCLUSIONS Tigatuzumab combined with sorafenib vs. sorafenib alone in adults with advanced hepatocellular carcinoma did not meet its primary efficacy end point, although tigatuzumab plus sorafenib is well tolerated in hepatocellular carcinoma.

Phase I Imaging and Pharmacodynamic Trial of CS-1008 in Patients With Metastatic Colorectal Cancer

PURPOSE CS-1008 (tigatuzumab) is a humanized, monoclonal immunoglobulin G1 (IgG1) agonistic antibody to human death receptor 5. The purpose of this study was to investigate the impact of CS-1008 dose on the biodistribution, quantitative tumor uptake, and antitumor response in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS Patients with mCRC who had received at least one course of chemotherapy were assigned to one of five dosage cohorts and infused with a weekly dose of CS-1008. Day 1 and day 36 doses were trace-labeled with indium-111 ((111)In), followed by whole-body planar and regional single-photon emission computed tomography (SPECT) imaging at several time points over the course of 10 days. RESULTS Nineteen patients were enrolled. (111)In-CS-1008 uptake in tumor was observed in only 12 patients (63%). (111)In-CS-1008 uptake and pharmacokinetics were not affected by dose or repeated drug administration. (111)In-CS-1008 biodistribution showed gradual blood-pool clearance and no abnormal uptake in normal tissue. No anti-CS-1008 antibody development was detected. One patient achieved partial response (3.7 months duration), eight patients had stable disease, and 10 patients had progressive disease. Clinical benefit rate (stable disease + partial response) in patients with (111)In-CS-1008 uptake in tumor was 58% versus 28% in patients with no uptake. An analysis of individual lesions showed that lesions with antibody uptake were one third as likely to progress as those without antibody uptake (P = .07). Death-receptor-5 expression in archived tumor samples did not correlate with (111)In-CS-1008 uptake (P = .5) or tumor response (P = .6). CONCLUSION Death-receptor-5 imaging with (111)In-CS-1008 reveals interpatient and intrapatient heterogeneity of uptake in tumor, is not dose dependent, and is predictive of clinical benefit in the treatment of patients who have mCRC.

Impact of race on dose selection of molecular-targeted agents in early-phase oncology trials

BackgroundWe examined the impact of race on the maximum tolerated doses (MTD) and final approved doses (FAD) of single-agent molecular-targeted agents (MTA) in North America/Europe (NA/EU) and Asia.MethodsWe searched PubMed and regulatory databases to identify targeted drugs approved globally and compared their FAD and MTD in corresponding phase I/II studies conducted separately in NA/EU and Asia. To evaluate this further, we conducted parallel, prospective, first-in-human studies of DS-7423, a dual PI3K/mTOR inhibitor, in patients with advanced solid tumours in the US and Japan. We pooled and compared the pharmacokinetics (PK), pharmacodynamics (PD), toxicity, and efficacy between these populations.Results17 MTA were approved in NA/EU and Asia from 2001 to 2015. Recommended phase 2 doses (RP2D) were identical across races in 14 of 17 (80%) studies and differences were not clinically meaningful. FAD were identical across all regions. 42 and 27 patients from US and Japan, respectively, were enrolled in the phase I studies of DS-7423. Despite differences in race, body weight, and body mass index, the RP2D were 240 mg/day with no differences in toxicities, PK, PD, or efficacy.ConclusionsConducting separate clinical trials of single-agent MTA in Caucasian and Asian populations may be redundant.

Abstract 4300: Receptor occupancy and tumor penetration by antibodies, peptides, and antibody fragments: Molecular simulation of imaging assessment

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: Non-uniform tumor penetration by antibodies may contribute to therapeutic failure. Competition experiments by radiolabeled antibody imaging can guide selection of the antibody dose that fully blocks target binding and thus corresponds to complete therapeutic coverage. However, because antibodies penetrate tumors slowly and non-uniformly, such a competition experiment may reflect only the most accessible sites. A novel approach, termed enhanced competition, has been proposed in which the radiolabeled moiety is smaller and more readily diffusible. In this study, simulations were conducted in order to examine the enhanced competition experiment. Materials and Methods: The Krogh cylinder distributed model was implemented to simulate the distribution of antibody, antibody fragment, affibody, or peptide in the tumor as a function of time and distance from the capillary wall. Simulations explored traditional and enhanced competition experiments, varying parameters including the nature of the small construct, time between administration of unlabeled and radiolabeled compounds, mass dose, affinity, antigen density, and internalization rate. Results were plotted as nanomolar concentration versus time and distance from the capillary wall. In addition, total tumor %ID/g is presented as a function of time and as a function of unlabeled antibody dose. Results: Simulation results showed that small constructs access sites in tumors at distances far from capillaries that are not readily accessible to intact antibodies. Under conditions of high affinity (1-10 nM), high antigen density (150,000 sites/cell), and compound internalization (t1/2 = 13 h), a mass of > 40 μg/kg of peptide or affibody construct required a higher dose of antibody to displace the radioactive signal compared to traditional competition with radiolabeled antibody. However, the difference in imaging signal between sub-saturating and fully displacing antibody doses is expected to be difficult to detect. Conclusions: The phenomenon predicted by the enhanced competition paradigm using small constructs is validated by modeling. Simulated imaging competition experiments indicate that affinity and mass dose levels are critical factors in this approach. High affinity small constructs and enhanced precision of imaging techniques will be required to fully evaluate target occupancy and saturation in vivo. Citation Format: Kelly D. Orcutt, Gregory P. Adams, Anna M. Wu, Matthew Silva, Jack Hoppin, Catey Harwell, Manabu Matsumura, Masakatsu Kotsuma, Daniel Freeman, Archie Tse, Jonathan Greenberg, Andrew Scott, Robert A. Beckman. Receptor occupancy and tumor penetration by antibodies, peptides, and antibody fragments: Molecular simulation of imaging assessment. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4300. doi:10.1158/1538-7445.AM2014-4300

Abstract LB-197: First-in-human study with ARQ 092, a novel pan AKT-inhibitor: Results from the advanced solid tumors cohorts.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background: ARQ 092 is an oral allosteric, ATP-independent, potent and selective inhibitor of AKT. Preclinical data from human cell lines and xenograft models support the exploration of anti-tumor activity of ARQ 092 across a broad range of human solid and hematological malignancies. The safety and preliminary activity of ARQ 092 in patients with advanced/metastatic solid tumors are presented. Methods: Adults patients (pts) were enrolled into this multi-cohort phase 1 trial at the starting dose of 10 mg/QOD. Cohorts of 3 or 6 patients were based on a 3+3 dose escalation schedule. Dose was to be doubled for the first 5 cohorts, then increased according to a modified Fibonacci scheme. Treatment was continued until disease progression or unacceptable toxicity. Diabetic patients requiring insulin were excluded. Dose Limiting Toxicity (DLT) definition included grade ≥3 toxicities, grade 2 liver dysfunction, and grade 3 hyperglycemia requiring insulin (uncontrolled by metformin) during the first 28 days of treatment. Results: As of October 20th, 2012, 22 ECOG PS1 pts (8 male; median age 63.3 yrs), with advanced/metastatic solid tumors were enrolled at doses/schedules ranging from 10 mg/QOD to 80mg/QD. Colorectal (N=4), endometrial (N=4) and neuroendocrine (N=3) were the most frequent tumors. Treatment-emergent adverse events (TEAEs) were reported in 20 (90.9%) pts. The most frequent (>10%) included nausea, fatigue (both in 10 pts, 45.4%) and anorexia (7 pts, 31.8%). Grade 3 maculo-papular rash with pruritis occurred in 2 pts in the 80mg/QD cohort, triggering one DLT. Eight pts experienced 17 SAEs including diarrhea, tricuspid regurgitation, dyspnea and metabolic encephalopathy. Drug-related SAEs include: Grade 3 hyperglycemia, in 3 pts at 80mg/QD (1 constituted DLT, another was not a DLT because it was not treated with metformin, and the third, managed with insulin, occurred after 28 days). A DLT of congestive heart failure developed in a subject previously exposed to radiation and adriamycin. The MTD has not been reached, but the 80mg QD continuous dose/schedule was deemed not to be well tolerated. A cohort of 60mg QD is under evaluation. Currently, 6 pts remain stable for > 4 months and 3 pts are still on therapy (1 pt on 80mg/QD, 2 pts on 20mg/QD); a 20% reduction in tumor burden was achieved in a pt with concomitant reduction of circulating pAKT expression. The study is ongoing with 7 pts on ARQ 092. PK analysis and PD results based on tumor biomarker expression and on plasma pAKT are pending. Conclusions: A formal MTD has not yet been reached. Rash preceded by hyperglycemia and preliminary signs of activity as single agent may represent a differential feature of ARQ 092 in this class. Exploratory efficacy in a selected population over-expressing AKT will be pursued at the defined recommended phase 2 dose. Citation Format: Mansoor Saleh, Kyri Papadopoulos, Alireza Arabnia, Amita Patnaik, Robin M. Stein, Federica Cattaneo, Giovanni Abbadessa, Jonathan Greenberg, Stephen Warren, Anthony Tolcher. First-in-human study with ARQ 092, a novel pan AKT-inhibitor: Results from the advanced solid tumors cohorts. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-197. doi:10.1158/1538-7445.AM2013-LB-197