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

Primary Purpose

Cancer, Solid Tumors, Lymphoma

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Debio 1143 (AT-406)

About this trial

This is an interventional treatment trial for Cancer focused on measuring cancer, solid tumors, lymphoma, smac mimetic, IAP inhibitor, Phase I, Dose escalation

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

University of Michigan Cancer Center
Mayo Clinic
Duke University Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Debio 1143 (AT-406)

Arm Description

Open label study. All patients participating in the study will receive Debio 1143 (AT-406).

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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).

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.

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.

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).

Full Information

NCT ID

NCT01078649

First Posted

March 1, 2010

Last Updated

December 26, 2018

Sponsor

Debiopharm International SA

1. Study Identification

Unique Protocol Identification Number

NCT01078649

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

December 2018

Overall Recruitment Status

Completed

Study Start Date

March 29, 2010 (Actual)

Primary Completion Date

April 2014 (Actual)

Study Completion Date

April 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Debiopharm International SA

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Cancer, Solid Tumors, Lymphoma, Malignancy

Keywords

cancer, solid tumors, lymphoma, smac mimetic, IAP inhibitor, Phase I, Dose escalation

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

51 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Debio 1143 (AT-406)

Arm Type

Experimental

Arm Description

Open label study. All patients participating in the study will receive Debio 1143 (AT-406).

Intervention Type

Drug

Intervention Name(s)

Debio 1143 (AT-406)

Intervention Description

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.

Primary Outcome Measure Information:

Title

Maximally Tolerated Dose

Description

Time Frame

1 cycle, or any time during treatment

Secondary Outcome Measure Information:

Title

Pharmacokinetic

Description

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).

Time Frame

Days 1-5 of Cycle 1

Title

Pharmacodynamic

Description

Time Frame

Cycle 1

Title

Efficacy

Description

Time Frame

After a minimum of 2 cycles.

Title

Correlation of Efficacy to Pharmacokinetic and/or Pharmacodynamic Effects of Debio 1143 (AT-406)

Description

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).

Time Frame

Anytime during Debio 1143 (AT-406) treatment

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Claudio Zanna, MD

Organizational Affiliation

Debiopharm SA

Official's Role

Study Director

Facility Information:

Facility Name

University of Michigan Cancer Center

City

Ann Arbor

State/Province

Michigan

ZIP/Postal Code

48109

Country

United States

Facility Name

Mayo Clinic

City

Rochester

State/Province

Minnesota

ZIP/Postal Code

55905

Country

United States

Facility Name

Duke University Medical Center

City

Durham

State/Province

North Carolina

ZIP/Postal Code

27710

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

25716544

Citation

Hurwitz HI, Smith DC, Pitot HC, Brill JM, Chugh R, Rouits E, Rubin J, Strickler J, Vuagniaux G, Sorensen JM, Zanna C. Safety, pharmacokinetics, and pharmacodynamic properties of oral DEBIO1143 (AT-406) in patients with advanced cancer: results of a first-in-man study. Cancer Chemother Pharmacol. 2015 Apr;75(4):851-9. doi: 10.1007/s00280-015-2709-8. Epub 2015 Feb 27.

Results Reference

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

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