Prasanna Kumar

Considerations in the development of circulating tumor cell technology for clinical use

This manuscript summarizes current thinking on the value and promise of evolving circulating tumor cell (CTC) technologies for cancer patient diagnosis, prognosis, and response to therapy, as well as accelerating oncologic drug development. Moving forward requires the application of the classic steps in biomarker development–analytical and clinical validation and clinical qualification for specific contexts of use. To that end, this review describes methods for interactive comparisons of proprietary new technologies, clinical trial designs, a clinical validation qualification strategy, and an approach for effectively carrying out this work through a public-private partnership that includes test developers, drug developers, clinical trialists, the US Food & Drug Administration (FDA) and the US National Cancer Institute (NCI).

Selective Targeting of Myeloid-Derived Suppressor Cells in Cancer Patients Using DS-8273a, an Agonistic TRAIL-R2 Antibody

Purpose: Myeloid-derived suppressor cells (MDSC) are one of the major contributors to immune suppression in cancer. We recently have demonstrated in preclinical study that MDSCs are sensitive to TRAIL receptor 2 (TRAIL-R2) agonist. The goal of this study was to clinically test the hypothesis that targeting TRAIL-R2 can selectively eliminate MDSCs. Experimental Design: The TRAIL-R2 agonistic antibody (DS-8273a) has been tested in 16 patients with advanced cancers enrolled in a phase I trial. The antibody (24 mg/kg) was administered intravenously once every 3 weeks till disease progression, unacceptable toxicities, or withdrawal of consent. The safety and the presence of various populations of myeloid and lymphoid cells in peripheral blood and tumor tissues were evaluated. Results: The treatment was well tolerated with only mild to moderate adverse events attributable to the study drug. Treatment with DS-8273a resulted in reduction of the elevated numbers of MDSCs in the peripheral blood of most patients to the levels observed in healthy volunteers. However, in several patients, MDSCs rebounded back to the pretreatment level by day 42. In contrast, DS-8273a did not affect the number of neutrophils, monocytes, and other populations of myeloid and lymphoid cells. Decrease in MDSCs inversely correlated with the length of progression-free survival. In tumors, DS-8273a treatment resulted in a decrease of MDSCs in 50% of the patients who were able to provide pre- and on-treatment biopsies. Conclusions: Targeting TRAIL-R2 resulted in elimination of different populations of MDSCs without affecting mature myeloid or lymphoid cells. These data support the use of this antibody in combination immmunotherapy of cancer. Clin Cancer Res; 23(12); 2942–50. ©2016 AACR.

Abstract B27: A phase I dose escalation study of the MDM2 inhibitor DS-3032b in patients with advanced solid tumors and lymphomas

Background: Reactivation of the tumor suppressor functions of p53 by targeting its negative regulator mdm2 represents an attractive approach to treat cancers expressing wildtype functional p53. DS-3032b disrupts the interaction between p53 and mdm2, and has demonstrated anti-tumor activity preclinically. Here, we report results from the Dose Escalation part (Part 1) of our Phase I Trial in solid tumors and lymphomas which aimed to determine a tentative recommended Phase 2 dose (tRP2D) and characterize the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of DS-3032b. Methods: DS-3032b dose was escalated using an accelerated titration followed by modified Continuous Reassessment Method and Escalation with Overdose Control design, from 15 mg through 30, 60, 120, 160, and 240 mg in a PO QD schedule in 21 of 28 days per cycle (QD 21/28). A 90 mg dose schedule of everyday administration (QD 28/28) had also been tested. Results: Thirty-one of 34 patients (pts) enrolled were evaluable for dose limiting toxicities (DLT). Of the 13 different tumors types enrolled, 77% were TP53 wildtype, with well-differentiated/de-differentiated (WD/DD) liposarcoma (LPS) being the most frequent (n = 13; 44%). The maximum tolerated dose (MTD) was determined to be 120 mg with 2/13 DLTs for the QD 21/28 schedule, which is currently being evaluated as the tRP2D in the Dose Expansion part (Part 2) of the study in more limited tumor types. The MTD was 90 mg with 1/9 DLT for the QD 28/28 schedule. The most common drug-related adverse events (AEs) were hematological (thrombocytopenia (Th) [68%], anemia [35%], neutropenia [29%] gastrointestinal (nausea [71%], vomiting [32%] and diarrhea [38%]), and fatigue [47%]. Prolonged Th resulting in >4 weeks dose interruption was seen in 8 pts, 2 were treated at the tRP2D. Bone marrow examination performed in selected pts revealed no dysplastic changes. A total of 6 pts experienced DLTs, all treated at MTD or higher. The 3 MTD DLTs were caused by Th that resulted in >1 week delay in starting Cycle 2. There was a moderate degree of inter-patient variability in PK exposure, with considerable overlap in exposures at the two MTDs (Cycle 1 Day 1 mean Cmax = 559.9 and 567.7 ng/mL, and mean AUC 0-24 = 8047.7 and 8629.3 ng*h/mL respectively for 120 and 90 mg doses). The steady state Cmin at MTDs exceeded the levels demonstrated as necessary for both disrupting MDM2-p53 interactions and showing antitumor activity preclinically. Induction of the PD biomarker MIC 1 in serum correlated with drug exposure. Twenty three pts were evaluable for tumor response. Most pts (20/26) experienced stable disease (SD) as the best tumor response though no pt had an objective response. The median progression free survival (mPFS) for all evaluable pts at 5.7 months, with 3 (1 carcinoid and 2 liposarcoma; all contain MDM2 amplification) still on study after receiving therapy for 12+, 20+, and 21+ cycles. The greatest tumor shrinkage and most durable SD were seen in pts with WD/DD LPS with mPFS of 6.3 months and 3-month PFS rate of 92%. Conclusions: DS-3032b shows an acceptable safety profile at the tRP2D of 120mg QD x 21/28. Preliminary evidence of clinical activity with prolonged PFS was seen in WD/DD LPS in which MDM2 is universally amplified, warranting further investigation in this disease. ClinicalTrials.gov Identifier: NCT01877382 Citation Format: Todd Bauer, David Hong, Neeta Somaiah, Charles Cai, Saeheum Song, Prasanna Kumar, Roohi Gajee, Michael Rosen, Jarema Kochan, Shuquan Chen, David Hyman, Tyler Masters, Funda Meric-Bernstam, Archie Tse, Patricia LoRusso, Amy Weise, Mrinal Gounder. A phase I dose escalation study of the MDM2 inhibitor DS-3032b in patients with advanced solid tumors and lymphomas. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B27.

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 CT095: The selective targeting of myeloid-derived suppressor cells in cancer patients using an agonistic TRAIL-R2 antibody

The goal of this current study was to clinically test the hypothesis that by targeting TRAIL-R2, myeloid-derived suppressor cells (MDSCs) can be selectively eliminated. MDSC) are one of the major contributors to immune suppression in cancer. We previously demonstrated in a preclinical study that MDSCs are sensitive to a TRAIL receptor 2 (TRAIL-R2) agonist. The TRAIL-R2 agonistic antibody (DS-8273a; provided by Daiichi Sankyo, Inc.) was tested in 16 patients with advanced solid cancers or lymphomas enrolled in a phase 1 trial. The antibody (24 mg/kg) was administered IV once every 3 weeks till disease progression, unacceptable toxicities, or withdrawal of consent. The safety and the presence of various populations of myeloid and lymphoid cells in peripheral blood and tumor tissues were evaluated using flow cytometry and immunohistochemistry. Overall, the treatment was well tolerated with only mild to moderate adverse events attributable to the study drug. Furthermore, treatment with DS-8273a resulted in reduction of the elevated numbers of MDSC in the peripheral blood of most patients to the levels observed in healthy volunteers. However, in several patients, MDSC rebounded back to the pre-treatment level by day 42. In contrast, DS-8273a did not affect the number of neutrophils, monocytes, and other populations of myeloid and lymphoid cells with decreases in MDSC levels inversely correlating with the length of progression-free survival. In tumors, DS-8273a treatment resulted in a decrease of MDSC in 50% of the patients who were able to provide pre- and on-treatment biopsies. In conclusion, targeting TRAIL-R2 using DS-8273a resulted in a temporary elimination of MDSCs without affecting mature myeloid or lymphoid cells, and these data support further use of this antibody in combination with current immmunotherapies of cancer. Citation Format: George A. Dominguez, Thomas Condamine, Sridevi Mony, Ayumi Hashimoto, Fang Wang, Qin Liu, Andres Forero, Johanna C. Bendell, Robert Witt, Neil Hockstein, Prasanna Kumar, Dmitry I. Gabrilovich. The selective targeting of myeloid-derived suppressor cells in cancer patients using an agonistic TRAIL-R2 antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT095. doi:10.1158/1538-7445.AM2017-CT095