Dose Escalation Study of Safety and Tolerability of AT-406 in Patients With Advanced Solid Tumors and Lymphomas

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety profile and the maximum dose of Debio 1143 (AT-406) that can be given to humans. This study is also designed to measure how much Debio 1143 (AT-406) gets into the blood stream (pharmacokinetics), and how Debio 1143 (AT-406) interacts with proteins related to cancer that the drug is targeted to affect (pharmacodynamics).

Detailed Description
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Ascenta Therapeutics, Inc. is conducting a clinical trial of the compound Debio 1143 (AT-406), a small molecule second mitochondria-derived activator of caspase C (Smac) mimetic. In vivo and in vitro studies have demonstrated that Debio 1143 (AT-406) induces cell death in several tumor models by inhibiting XIAP (X linked IAP), cIAP-1 (cellular IAP-1) and cIAP-2 (cellular IAP-2), thus releasing initiator and effector caspases to promote apoptosis. This protocol is a Phase I, dose-escalation, open-label, multi-center study conducted in patients with advanced solid tumors and lymphomas to evaluate the safety, tolerability and pharmacology of Debio 1143 (AT-406) in humans when administered orally.

Official Title
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A Phase I, Open Label, Multi-Center, Dose Escalation Study of the Safety, Tolerability, Pharmacodynamic and Pharmacokinetic Properties of Orally Administered AT-406 in Patients With Advanced Solid Tumors and Lymphomas

Conditions
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Cancer, Solid Tumors, Lymphoma, Malignancy

Intervention / Treatment
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* Drug: Debio 1143 (AT-406)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed solid tumor or lymphoma; Locally advanced or metastatic disease for which no life prolonging therapy is available and no standard therapy is judged appropriate by the investigator; Eastern Cooperative Oncology Group Performance Status ≤ 1; Adequate hematologic function as indicated by, ANC ≥ 1,500/mm3, Hgb >9.0 g/dL, platelet count ≥ 100,000/mm3 Adequate renal and liver function as indicated by serum creatinine ≤ 1.0 x ULN or creatinine clearance of > 60 cc/min, serum albumin ≥ 3.0 gm/dL, total bilirubin < 1.0 x ULN, AST and ALT ≤ 2.5 x ULN ; Alkaline phosphatase ≤2.5 x ULN Negative Hepatitis B and Hepatitis C testing; QTc interval ≤450ms. Exclusion Criteria: Radiation within 14 days of study entry, thoracic radiation within 28 days of study entry. Patients who have received prior radiotherapy must have discontinued steroids for 14 days prior to study entry and be clinically stable; Not recovered to ≤ Grade 1 toxicity from prior radiotherapy or chemotherapy agents; Use or requirement for use of aspirin or aspirin containing products with >81 mg of aspirin per day; History of gastrointestinal bleeding within 1 year; History of diabetes mellitus requiring treatment with oral agents or insulin; Active rheumatoid arthritis, active inflammatory bowel disease, chronic infections, or any other disease or condition associated with chronic inflammation; Known or suspected Wilson's Disease, or other conditions that affect copper accumulation or regulation; Prior treatment with IAP inhibitors.

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: Debio 1143 (AT-406)<br>Open label study. All patients participating in the study will receive Debio 1143 (AT-406). | Drug: Debio 1143 (AT-406)<br>* Oral Debio 1143 (AT-406) will be administered in a dose escalation study to determine the maximally tolerated dose in humans. Patients will receive Debio 1143 (AT-406) on days 1-5, and 15-19 of a 28 day cycle, or days 1-5 of a 21 day cycle, repeated until progression or unacceptable toxicity occurs.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximally Tolerated Dose | The primary endpoint of this study is to characterize the safety, and determine the maximum tolerated dose and schedule of Debio 1143 (AT-406) when administered to patients with advanced cancer. Patients will receive Debio 1143 (AT-406) on days 1-5, and 15-19 of a 28 day cycle, days 1-5 of a 21 day cycle, or days 1-14 of a 21 day cycle. For the purpose of determining the MTD, dose limiting toxicities will be evaluated at any time. For the purpose of dose escalation, dose limiting toxicities will be evaluated through the end of 1 cycle. | 1 cycle, or any time during treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic | A secondary endpoint of this study is to determine the pharmacokinetic parameters of Debio 1143 (AT-406) in plasma and urine, and preliminary metabolism profile of Debio 1143 (AT-406). | Days 1-5 of Cycle 1 | 
| Pharmacodynamic | A secondary endpoint of this study, provided that adequate amounts of tissue are available, is to evaluate the interaction of Debio 1143 (AT-406) with IAP family members (e.g., xIAP, cIAP-1, cIAP-2, etc.). Patient participation in this aspect of the study is optional. | Cycle 1 | 
| Efficacy | A secondary endpoint to this study is to identify any anti-tumor activity of Debio 1143 (AT-406) that may be observed in the course of the trial. Applicable solid tumor or lymphoma response criteria will be used, accordingly. | After a minimum of 2 cycles. | 
| Correlation of Efficacy to Pharmacokinetic and/or Pharmacodynamic Effects of Debio 1143 (AT-406) | A secondary endpoint of this study is to correlate pharmacokinetic and pharmacodynamic effects of Debio 1143 (AT-406) with any observed antitumor activity of Debio 1143 (AT-406). | Anytime during Debio 1143 (AT-406) treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cancer, solid tumors, lymphoma, smac mimetic, IAP inhibitor, Phase I, Dose escalation