A Dose Escalation and Expansion Study of ASP4132 to Subjects With Advanced Refractory Tumors and Lymphoma

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and tolerability of ASP4132 and to determine the maximum tolerated dose and recommended phase 2 dose of ASP4132. The study will also determine the pharmacokinetics (PK) of ASP4132 and evaluate the preliminary antitumor activity.

Detailed Description
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The study consists of two parts and these will be conducted sequentially: Part 1 (dose escalation) and Part 2 (dose expansion). Subjects will participate in Part 1 or Part 2.

Official Title
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An Open-Label, Dose-Escalation/Expansion Phase 1 Study of ASP4132 Given Orally to Patients With Advanced Refractory Solid Tumors and Lymphoma

Conditions
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Lymphoma, Refractory Solid Tumors, Advanced Cancer

Intervention / Treatment
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* Drug: ASP4132


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject has a life expectancy of more than 3 months Subject agrees not to participate in another interventional study while on treatment. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. Female subject must be either: Of non-child bearing potential: post-menopausal (defined as at least 1 year without any menses) prior to Screening, or, documented surgically sterile or status post hysterectomy Or, if of childbearing potential, agree not to try to become pregnant during the study and for 90 days after the final study drug administration; if heterosexually active must use two forms of birth control Male subject and their female spouse/partners who are of childbearing potential must be using highly effective contraception consisting of two forms of birth control (one of which must be a barrier method) starting at Screening and continue throughout the study period and for 90 days after the final study drug administration. Subject must have advanced and/or metastatic, histologically or cytologically documented cancer or lymphomas, for whom there is no available standard therapy shown to provide clinical benefit. Exclusion Criteria: Subject has absolute neutrophil count < 1000/μL, platelet count < 75,000/μL, and hemoglobin < 8 g/dL (< 5 mmol/L) at Screening Subject has total serum bilirubin ≥1.5 times the upper limit of normal (ULN),serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) > 3 times ULN, or albumin ≤ 3.0 g/dL at Screening. Subject has any abnormalities in serum sodium, potassium, chloride, calcium and magnesium levels ≥ Grade 2 at screening (CTCAE Version 4.03). Subject has a known elevation in serum lactate at screening ˃ 2x institutional ULN Subject has an estimated glomerular filtration rate (eGFr) of < 60ml/min as calculated by the modification of diet Renal disease (MDRD) Equation. Subject with a QTcF of > 450 msec in male subjects and > 470 msec in female subjects on the screening 12 lead ECG. Subject has Neuropathy ≥ Grade 2 at Screening. Subject has Type 1 Diabetes Mellitus or Type 2 Diabetes Mellitus and currently being treated with insulin or sulfonylureas. Subject has concomitant active second malignancies unless remission was achieved at least 3 years prior to study entry and subject is no longer on therapy for the malignancy. Subject has a significant cardiovascular disease Subject has a known history of acute or chronic hepatitis B (HBV), HIV or hepatitis C (HCV) infection. Subject has serious/active bacterial, viral or fungal infection requiring systemic treatment. Subject has significant gastrointestinal abnormalities, including ulcerative colitis, chronic diarrhea associated with intestinal malabsorption, Crohn's disease, and/or prior surgical procedures affecting absorption or requirement for intravenous (IV) alimentation. Subject has active central nervous system (CNS) metastases not controlled by prior surgery or radiotherapy (subjects must be off steroids). Subjects with signs or symptoms suggestive of brain metastasis are not eligible unless brain metastases are ruled out by brain MRI/CT. Subject has concurrent severe or uncontrolled medical disease or organ system dysfunction which, in the opinion of the Investigators, would limit life expectancy to < 3 months. Subject has psychiatric disorder or altered mental status that would preclude an understanding of the informed consent process and/or completion of the necessary study procedures. Subject has difficulty swallowing large pills. Subject currently being treated with biguanides or other agents known to increase risk of lactic acidosis. Subject has unavoidable concomitant treatment with any drug known for causing Torsades de Pointes. Subject has had radiotherapy or surgery within the 4 weeks prior to treatment with ASP4132. Subject has not discontinued all previous systemic therapies for cancer including chemotherapy, immunotherapy, or biological therapies for at least 14 days prior to the initiation of ASP4132. Subject has not fully recovered from the acute toxicities (except alopecia) of any prior anti-cancer therapy. Subject requiring concomitant use of strong CYP3A4 inhibitors or inducers.

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ASP4132 dose escalation<br>Subjects will receive a single dose of the study drug on Day -4 (Single-Dose Period), followed by PK sampling prior to Multiple-Dose Period where they will receive the same dose as they received in the Single-Dose Period on one of four schedules: Continuous - daily dosing for 28 days, Intermittent: Schedule A: 3 days on / 4 days off; Schedule B: 1 days on / 6 days off; Schedule C: 3 days on / 11 days off. | Drug: ASP4132<br>* oral<br>|
| Experimental: ASP4132 dose expansion<br>Subjects in Part 2 will be treated with ASP4132 at the MTD and dosing schedule identified from Part 1. | Drug: ASP4132<br>* oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety as assessed by adverse events |  | up to 39 months | 
| Safety as assessed by clinical laboratory tests |  | up to 39 months | 
| Safety as assessed by vital signs |  | up to 39 months | 
| Safety as assessed by electrocardiograms (ECG) |  | up to 39 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate to ASP4132 |  | Week 16 | 
| Duration of response to ASP4132 |  | Week 16 | 
| Disease control rate to ASP4132 |  | Week 16 | 
| Maximum concentration (Cmax) of ASP4132 |  | up to 43 days | 
| Time of the maximum concentration (Tmax) of ASP4132 |  | up to 43 days | 
| Area under the concentration-time curve from time of dosing to the last measurable concentration (AUClast) of ASP4132 |  | up to 43 days | 
| AUC from the time of dosing to 24 hours (AUC24) of ASP4132 |  | up to 43 days | 
| AUC from the time of dosing extrapolated to time infinity (AUCinf) of ASP4132 |  | up to 43 days | 
| Apparent terminal elimination half-life (T1/2) of ASP4132 |  | up to 43 days | 
| Accumulation ratio of ASP4132 |  | up to 43 days | 
| Apparent total systemic clearance after single or multiple extravascular dosing (CL/F) of ASP4132 |  | up to 43 days | 
| Apparent volume of distribution during the terminal elimination phase after single or multiple extravascular dosing (Vz/F) of ASP4132 |  | up to 43 days | 
| Progression-free survival |  | up to 39 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pharmacokinetics, ASP4132, Lymphoma, Refractory Solid Tumors