A Open-Label, Multiple Ascending Dose Study of DS-3078a, an Oral TORC1/2 Kinase Inhibitor, in Subjects With Advanced Solid Tumors or Lymphomas

Study Overview
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Brief Summary
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DS-3078a will be evaluated as a single agent in subjects with advanced solid tumor malignancies or lymphomas refractory to standard treatment or for which no standard treatment is available.

Detailed Description
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This is a Phase 1, open-label study of DS-3078a to assess safety and tolerability, identify the maximum tolerated dose (MTD) and tentative recommended phase 2 dose (RP2D), and assess pharmacokinetic and pharmacodynamic properties in subjects with advanced solid tumor malignancies or lymphomas. The study will include 2 parts: Dose Escalation and Dose Expansion.

Official Title
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A Phase 1, Open-Label, Multiple Ascending Dose Study of DS-3078a, an Oral TORC1/2 Kinase Inhibitor, in Subjects With Advanced Solid Tumors or Lymphomas

Conditions
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Advanced Solid Tumor, Lymphoma

Intervention / Treatment
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* Drug: DS-3078a


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A pathologically or cytologically documented advanced solid tumor or lymphoma that has relapsed from or is refractory to standard treatment or for which no standard treatment is available. Men or women >=18 years old. Eastern Cooperative Oncology Group (ECOG) performance status =<1 Have adequate bone marrow function, defined as: Platelet count >=100 x 10^9/L for solid tumors and >=75 x 10^9/L for lymphomas, Hemoglobin level >=9.0 g/dL, and ANC >=1.5 x 10^9/L for solid tumors and >=1.0 x 10^9/L for lymphomas. Have adequate renal function, defined as: Creatinine clearance >=60 mL/min, or creatinine =<1.5 x ULN. Have adequate hepatic function, defined as: AST/ALT levels =<3 x ULN (=<5 x ULN if liver metastases are present) and Bilirubin =<1.5 x ULN. Have adequate blood clotting function, defined as prothrombin time and activated partial thromboplastin time =<1.5 x ULN. Subjects must be fully informed about their illness and the investigational nature of the study protocol (including foreseeable risks and possible side effects) and must sign and date an Institutional Review Board/Ethics Committee-approved informed consent form (including Health Insurance Portability and Accountability Act authorization, if applicable) before performance of any study specific procedures or tests. For Part 2 A pathologically or cytologically documented advanced solid tumor or non-Hodgkin lymphoma, with measurable disease based on RECIST 1.1 or revised IWG criteria, that is refractory to standard treatment. The solid tumor types that will be included in the study are of the following kinds in which the mTOR signaling is frequently activated: endometrial, prostate, breast, gastric, cervical,ovarian, or neuroendocrine cancers, soft-tissue sarcoma, squamous cell NSCLC,renal cell carcinoma or other tumor types approved by the Sponsor. Agree to undergo pre- and post-treatment tumor biopsies. Exclusion Criteria: History of primary central nervous system malignancies Gastrointestinal diseases that could affect the absorption of DS-3078a in the opinion of the Investigator Subjects with a fasting glucose >126 mg/dL (>7 mmol/L) History of diabetes mellitus (type 1 or 2) or glycosylated hemoglobin >7.0% at screening Positive test for hepatitis B surface antigen or hepatitis C antibody Recipient of live vaccine within 1 month of or during study drug treatment Use of chronic systemic corticosteroids (use of nasal or inhaled steroids is permitted) Subjects requiring daily supplemental oxygen Recipient of an allogenic stem cell or bone marrow transplant Presence of a concomitant medical condition that would increase the risk of toxicity, in the opinion of the Investigator or Sponsor Clinically active brain metastases, defined as untreated and symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms. Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to NCI-CTCAE v4 grade =<1 or baseline. Systemic treatment with anticancer therapy, antibody-based therapy, retinoid therapy, or hormonal therapy within 3 weeks before study drug treatment; or treatment with nitrosoureas or mitomycin C within 6 weeks before study drug treatment; or treatment with small-molecule targeted agents within 2 weeks or 5 half-lives before study drug treatment, whichever is longer. Therapeutic radiation or major surgery within 4 weeks before study drug treatment or palliative radiation therapy within 2 weeks before study drug treatment Participation in a clinical study within 3 weeks (2 weeks or 5 half-lives, whichever is longer, for small-molecule targeted agents) before study drug treatment, or current participation in other investigational procedures Concomitant treatment with strong inhibitors or inducers of cytochrome P450 3A4 and P glycoprotein Less than 1 week since using systemically acting drugs that increase gastric pH, such as H2-blockers and proton pump inhibitors. Antacids should be avoided within 48 hours of the first dose of DS 3078a Prolongation of corrected QT interval by Fridericia's method (QTcF) at rest, where the mean QTcF interval is >450 msec based on triplicate electrocardiogram (ECG) Pregnant or breastfeeding Substance abuse or medical, psychological, or social conditions that, in the opinion of the Investigator, may interfere with the subject's participation in the clinical study or evaluation of the clinical study results For Part 2 Subjects who have had prior treatment with an mTOR catalytic site inhibitor or dual PI3K/mTOR inhibitor (including, but not limited to, OSI-027, INK128, ADZ8055,AZD2014, WYE12513, PP242, BEZ-235, DS-7423, XL765, GDC-0980, SF1126, GSK2126458, PF4691502, and PF05212384) will be disqualified from entering the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DS-3078a<br>Part 1 - Dose escalation of DS-3078a to determine the maximum tolerated dose (MTD) will be guided by the modified continuous reassessment method (mCRM) using a Bayesian logistic regression model (BLRM) following escalation with overdose control (EWOC) principle. Before starting mCRM, initial dose escalation will proceed following an accelerated titration in which single subjects will be enrolled into sequential dose levels with a dose increment of up to 100% from the previous dose. Upon completion of Part 1 with established MTD and tentative recommended phase 2 dose (RP2D), the Dose Expansion (Part 2) will begin with the intention of further assessing the safety and tolerability of DS-3078a, confirming the RP2D, determining the Pharmacodynamic response in tumor samples, and evaluating preliminary efficacy of DS-3078a in subjects. | Drug: DS-3078a<br>* DS-3078a will be administered as oral capsules once daily and will be supplied in 5, 20, 50, and 150 mg capsules.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose | To determine the maximum tolerated dose (MTD) and tentative recommended Phase 2 dose (RP2D) of DS 3078a | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| determine the Cmax profile of DS 3078a | determine the Cmax (maximum concentration) of DS-3078a administered under fed and unfed conditions | 3 years | 
| effect on glucose metabolism | determine the effect of DS-3078a on glucose metabolism by measuring serum glucose and C peptide | 3 years | 
| assess pharmacodynamic effects tumor glucose uptake | assess the pharmacodynamic effects of DS 3078a by determining tumor glucose uptake using (18F) fluorodeoxyglucose positron emission tomography (FDG-PET) | 3 years | 
| assess tumor response | assess tumor response to DS-3078a in subjects with advanced non-Hodgkin lymphomas or advanced solid tumor types in which the mammalian target of rapamycin (mTOR) signaling pathway is frequently activated | 3 years | 
| assess pharmacodynamic effects v-akt murine thymoma viral oncogene | assess the pharmacodynamic effects of DS 3078a by measuring v-akt murine thymoma viral oncogene homolog 1 (Akt) phosphorylation in platelet rich plasma (PRP) | 3 years | 
| determine the AUC of DS 3078a | determine the Area under the concentration versus time curve (AUC) of DS-3078a administered under fed and unfed conditions | 3 years | 
| determine the Tmax of DS 3078a | determine the time of maximum concentyration (Tmax) of DS-3078a administered under fed and unfed conditions | 3 years | 
| determine the terminal half-life of DS 3078a | determine the terminal half-life (T1/2) of DS-3078a administered under fed and unfed conditions | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ovarian, endometrial, prostate, breast, gastric, cervical, neuroendocrine cancers, soft-tissue sarcoma, squamous cell NSCLC, renal cell carcinoma, non-Hodgkin lymphoma