Roohi Gajee

A Phase 1 Study in Healthy Subjects to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Multiple Oral Doses of DS-2969b, a Novel GyrB Inhibitor

ABSTRACT DS-2969b is a novel GyrB inhibitor in development for the treatment of Clostridium difficile infection (CDI). The aim of this study was to assess the safety, tolerability, pharmacokinetics, and effects on the normal gastrointestinal microbiota of multiple daily oral ascending doses of DS-2969b in healthy subjects. The study enrolled three sequential ascending-dose cohorts (60 mg, 200 mg, and 400 mg). In each cohort, subjects received an oral dose of DS-2969b or placebo (six subjects received DS-2969b, and two received placebo) each morning for 14 days. DS-2969b was safe and well tolerated at all dose levels examined. All adverse events related to DS-2969b were mild and predominantly related to the gastrointestinal tract. DS-2969a (free form of DS-2969b) plasma concentrations increased with increasing doses; however, both the maximum concentration of drug in serum (Cmax) and the area under the concentration-time curve (AUC) increased less than dose proportionally. In all cohorts, sufficient fecal levels of DS-2969a were achieved within 24 h following the administration of the first dose and maintained for at least 17 days. Following treatment with DS-2969b, clear reductions in the populations of Clostridium coccoides and Bifidobacterium groups were observed. However, populations of three other bacterial groups examined (Bacteroides fragilis, Clostridium leptum, and Prevotella) were not affected. Data from this study support and encourage the further development of DS-2969b as a novel treatment for CDI.

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.

A Phase I, Single‐Ascending‐Dose Study in Healthy Subjects to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DS‐2969b, a Novel GyrB Inhibitor

DS‐2969b is a novel GyrB inhibitor in development for the treatment of Clostridium difficile infection. The aim of this study was to assess the safety, tolerability, pharmacokinetics, and effects on normal gastrointestinal microbiota groups of single daily oral ascending doses of DS‐2969b in healthy subjects. The study enrolled 6 sequential ascending dose cohorts (6 mg, 20 mg, 60 mg, 200 mg, 400 mg, and 600 mg). In each cohort, 6 subjects were administered DS‐2969b and 2 subjects were administered matching placebo. DS‐2969b was safe and well tolerated at all dose levels examined. All adverse events related to DS‐2969b were mild to moderate in severity and predominantly related to the gastrointestinal tract. DS‐2969a (free form of DS‐2969b) plasma concentrations increased with increasing doses; however, both the maximum serum concentration and area under the plasma concentration–time curve generally increased less than dose proportionally. DS‐2969a was predominantly eliminated in the urine, with feces as a minor route of elimination. While the overall proportion of DS‐2969a eliminated in the feces was low, target fecal levels sufficient for C. difficile eradication were achieved within 24 hours of administration with doses of 60 mg or higher. In exploratory analyses, DS‐2969b appeared to reduce bacterial counts in 8 of the 25 groups of normal intestinal microbiota examined, suggesting that DS‐2969b has only a mild effect on intestinal microbiota. Data from this study support and encourage further development of DS‐2969b as a novel treatment for C. difficile infection.

Abstract CT024: First-in-human phase 1 dose-escalation study of DS-6051b, an oral ROS1 and NTRK inhibitor, in subjects with advanced solid tumors

Background: DS-6051b is an orally available small molecule receptor tyrosine kinase inhibitor with high affinity for the ROS1 and NTRK receptors. Non-clinical pharmacology studies demonstrated activity of DS-6051b against tumors harboring ROS1 or NTRK fusion genes in cell culture and xenograft models. The objectives of this first in human (FIH) study are to assess safety and tolerability of DS-6051b in cancer subjects and identify the maximum tolerated dose (MTD) and the tentative RP2D. Pharmacokinetics (PK), QT prolongation, and tumor responses are also assessed in this study (Clinical Trial Information: NCT02279433). Methods: Dose escalation initially followed an accelerated titration design enrolling a single subject at each dose level, and then adopted the modified continuous reassessment method using a Bayesian logistic regression model and escalation with overdose control. Adult subjects with advanced solid tumors harboring ROS1 or NTRK1-3 fusion genes; or with neuroendocrine carcinoma; or with advanced solid tumors with tumor-induced pain are eligible for the study. DS-6051b is orally administered once-daily in 21-day cycles. Tumor assessments are performed every 3 cycles using RECIST 1.1 criteria. Plasma PK samples and time-matched ECG data are collected at multiple time points. Results: A total of 22 subjects have been enrolled at 50, 100, 200, 400, 800, and 1200 mg once daily (QD) dose levels. Enrolled population included 11 subjects with neuroendocrine carcinomas, 9 subjects with advanced solid tumors with tumor-induced pain, 1 subject with ROS1 fusion-positive NSCLC liver metastases, and 1 subject with leiomyosarcoma with a ROS1 point mutation. Two dose-limiting toxicities occurred in subjects who received 1200 mg QD, consisting of grade 3 transaminase elevations. The MTD is 800 mg QD. The most frequent (?20%) TEAEs were diarrhea, nausea, vomiting, dehydration, dizziness, dysgeusia, and fatigue, which were predominantly grade ?2. Cmax and AUC increased with the dose. Plasma terminal half-life was 11-24 hours. Steady state AUC was approximately 3 to 4-fold higher than that of Cycle 1 Day 1. Two subjects showed partial response: One with neuroendocrine carcinoma, who received 800 mg QD (33% decrease in tumor size), and one with ROS1 fusion-positive NSCLC liver metastases, who received 1200 mg QD (44% decrease in tumor size). Notably, the latter subject had progressed on crizotinib (best objective response stable disease) and ceritinib (progressive disease). Conclusions: DS-6051b has been well tolerated up to 800 mg QD in subjects with advanced solid tumors. The observed efficacy signals in two subjects with partial response warrant further evaluation. This trial is now selectively accruing subjects with ROS1 fusion-positive tumors. Citation Format: Kyriakos P. Papadopoulos, Erkut Borazanci, Daniel Von Hoff, Leena Gandhi, Amita Patnaik, Masaya Tachibana, Hamim Zahir, Roohi Gajee, Terri Goldberg, Giorgio Senaldi, Sai-Hong Ou. First-in-human phase 1 dose-escalation study of DS-6051b, an oral ROS1 and NTRK inhibitor, in subjects with advanced solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT024.

Abstract C85: Drug interaction study of tivantinib in cancer subjects using a cocktail approach.

Background: Tivantinib (ARQ197) is an orally administered cMET inhibitor currently under development as a cancer therapy. Nonclinical studies have indicated that tivantinib and its major metabolites have the potential to inhibit cytochrome P450 (CYP) 3A4, 2C19, 2C9, and 1A, and the P-glycoprotein (P-gp) at the clinical concentrations being studied in phase 3 studies. The objective of this drug interaction study was to assess the effect of tivantinib at steady state levels on the pharmacokinetics of CYP- and P-gp-specific probe drugs (modified Cooperstown 5 + 1 Cocktail) after multiple BID doses of tivantinib. Methods: This was a phase 1, open-label, single-sequence, crossover study ([NCT01517399][1]) in subjects with advanced solid tumors. Each subject was administered five probe drugs in the absence or presence of tivantinib (360 mg BID): midazolam (CYP3A4), omeprazole (CYP2C19), S-warfarin (CYP2C9), caffeine (CYP1A), and digoxin (P-gp). Serial blood samples were collected to determine the pharmacokinetics of the probe drugs. Pharmacokinetic parameters were computed using a non-compartmental approach. Log-transformed pharmacokinetic parameters were analyzed using a linear mixed-effects model with treatment as fixed effects and subject as a random effect, and the ratio of geometric least-square (LS) means and the 90% CI for test treatment (Probe drug administered with tivantinib) to reference treatment (probe drug administered alone) were calculated. No drug interaction was concluded if the 90% CI of the LS mean ratios are within the range of 0.8-1.25. Results: Twenty eight cancer subjects were enrolled. The ratios of geometric LS mean (90% CI) for total exposure parameter (AUClast) were as follows: midazolam, 0.83 (0.67, 1.02); omeprazole, 0.89 (0.60, 1.31); S[[Unable to Display Character: ‑]]warfarin, 0.88 (0.76, 1.02); caffeine, 0.97 (0.89, 1.05); and digoxin, 0.69 (0.51, 0.94). Small changes in exposure were observed for midazolam, omeprazole, and warfarin with AUClast decreased ∼17%. Consistent with decrease in omeprazole AUClast (∼11.1%), the mean omeprazole/5-hydroxyomeprazole AUC ratio decreased by 12.8%. For digoxin, mean AUClast decreased by 30.9%. No interaction was determined on the caffeine pharmacokinetics. The effect on peak exposures (Cmax) was similar to the effect on AUClast. Treatment with tivantinib in combination with probe drugs omeprazole/warfarin/caffeine/midazolam or digoxin was generally well tolerated. Conclusion: These results suggested that coadministration of tivantinib 360 mg BID has a small or no effect on the pharmacokinetics of probe drugs used in this study. It is likely that the observed effect of tivantinib on CYP1A2, CYP2C9, CYP2C19, CYP3A4 and P-gp is of minimal clinical significance. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C85. Citation Format: Masaya Tachibana, Kyriakos P. Papadopoulos, John Strickler, Igor Puzanov, Roohi Gajee, Yibin Wang, Hamim Zahir. Drug interaction study of tivantinib in cancer subjects using a cocktail approach. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C85. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01517399&atom=%2Fmolcanther%2F12%2F11_Supplement%2FC85.atom