Tinostamustine Conditioning and Autologous Stem Cell

NCT ID: NCT03687125

Last Updated: 2021-06-18

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 6 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-10-15
• Study Completion Date: 2019-04-17

Brief Summary

Phase 1

The primary objectives of Phase 1 of this study are to:

• Establish the safety, toxicity, and maximum tolerated dose (MTD) of the tinostamustine conditioning regimen.
• Identify the recommended Phase 2 dose (RP2D) of tinostamustine for use in the Phase 2 portion of the study.

The secondary objective of Phase 1 of this study is to:

• Investigate the pharmacokinetics (PK) of tinostamustine.

Detailed Description

Study Design (Methodology):

This is a 2-part, international, multi-center, open-label study of salvage treatment with tinostamustine conditioning followed by ASCT in participants with relapsed/ refractory multiple myeloma (MM). (ASCT is defined as salvage if the participant had already received a prior ASCT and undergoes a second ASCT after evidence of progressive disease [PD].) Phase 1 of the study employs a standard 3+3 dose escalation design with the objective of defining the dose limiting toxicities (DLTs) of the tinostamustine conditioning regimen and defining the MTD and RP2D for use in the Phase 2 portion of the study.

The Safety Review Committee can make a decision to stop dose escalation or explore intermediary doses at any time. The total dose of tinostamustine will be administered on Day -1. Phase 2 of the study employs a 2-step sequential design (Simon, 1989). In Stage 1 of Phase 2, up to 31 participants initially will be enrolled. If lesser than or equal to (<=) 25 participants of these initial 31 participants experience a response, then no additional participants will be enrolled. However, if greater than (>) 25 participants in Stage 1 of Phase 2 experience a response, then enrollment in this cohort will continue, with up to 71 participants enrolled. In Phase 2 of the study, all participants will receive tinostamustine at the RP2D administered in Phase 1 according to the same schedule. After provision of written informed consent, participants will be screened for study eligibility within 28 days before Day 1 (the day of ASCT). Participants who have a minimum of 2×106 CD34+ cells/kg cryopreserved and are otherwise determined to be eligible, based on screening assessments, will be enrolled and receive the tinostamustine conditioning regimen. The tinostamustine dose will be administered 24 hours pre-ASCT (i.e., Day -1). On Day 1, ASCs will be administered intravenously (IV) according to standard institutional practice. Participants will receive supportive measures (including growth factor support post-ASCT, antimicrobial prophylaxis, red blood cell and platelet transfusion, and treatment for neutropenic fever) according to standard institutional practice.

Conditions

Multiple Myeloma in Relapse; Multiple Myeloma Progression; Multiple Myeloma With Failed Remission

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Tinostamustine 180 mg/m^2

Participants received single dose of tinostamustine 180 milligrams per meter square (mg/m\^2) intravenous (IV) injection on Day -1 followed by autologous stem cell transplantation (ASCT) on Day 1.

Group Type: EXPERIMENTAL

Tinostamustine

Intervention Type: DRUG

Participants received tinostamustine IV injection.

Autologous Stem Cell Transplant (ASCT)

Intervention Type: PROCEDURE

Undergo autologous stem cell transplant

Tinostamustine 220 mg/m^2

Participants received single dose of tinostamustine 220 mg/m\^2 IV injection on Day -1 followed by ASCT on Day 1.

Group Type: EXPERIMENTAL

Tinostamustine

Intervention Type: DRUG

Participants received tinostamustine IV injection.

Autologous Stem Cell Transplant (ASCT)

Intervention Type: PROCEDURE

Undergo autologous stem cell transplant

Interventions

Tinostamustine

Participants received tinostamustine IV injection.

Intervention Type: DRUG

Autologous Stem Cell Transplant (ASCT)

Undergo autologous stem cell transplant

Intervention Type: PROCEDURE

Eligibility Criteria

Inclusion Criteria

1. Participants has Multiple Myeloma (MM) and:

a. Has received prior ASCT after standard first-line induction treatment. b. Has evidence of progressive disease (PD), with progression-free interval greater than or equal to (>=) 6 months in Phase 1 >= 18 months in Phase 2.

• Progression Free Interval is defined as the time from date of ASCT to PD. c. Received treatment with lesser than or equal to (<=) 3 prior lines of therapy.
• A line of therapy is defined as 1 or more cycles of a planned treatment program. When participants have undergone sequential phases of treatment without intervening progression, such as induction, collection of peripheral blood stem cells (PBSCs), transplantation and consolidation/maintenance, this is considered to be 1 line of treatment. A new line of therapy is initiated as a result of PD or relapse.

2. Complete response (CR), very good partial response (VGPR), partial response (PR), or minimal response (MR) to salvage chemotherapy, as determined by the International Myeloma Working Group (IMWG) criteria.

3. Is, in the Investigator's opinion, a candidate for consolidation therapy with tinostamustine followed by ASCT. (Note that participants planned to receive tandem ASCT are not eligible for the Phase 1 portion of the study.)

4. Has available autologous peripheral blood stem cell (PBSC) product with CD34 cell dose >= 2×106 cells/kg. The product could be from a collection prior to first ASCT or later second collection. (Note that, although not required, in Phase 1, the Investigator should consider enrolling participant with a large number of available PBSCs to permit subsequent ASCT, as participants in Stage 1 may received a dose lower than that determined to be effective.)

5. Age 18-75 years.

6. Eastern Cooperative Oncology Group (ECOG) performance status score lesser than (<) 3 at Screening.

7. Creatinine clearance >= 40 milliliter per minute (mL/min), as determined by a local laboratory using the Cockcroft-Gault equation within 28 days before ASCT.

8. Left ventricular ejection fraction (LVEF) >= 40 percent (%) within 28 days before ASCT.

9. Adequate pulmonary function, defined as forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and carbon monoxide diffusing capacity (DLCO) greater than (>) 50% predicted within 28 days before ASCT.

10. Adequate liver function, as defined by an alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <= 2.5 × the upper limit of normal (ULN) and bilirubin <= 1.5 × ULN within 28 days before ASCT.

11. Potassium within the local laboratory's normal range. (Potassium supplementation is permissible.)

Exclusion Criteria

Participants meeting any of the following criteria are not eligible for study entry:

1. History of central nervous system (CNS) disease involvement.

2. Primary or secondary plasma cell leukemia at any time point prior to transplant.

3. Myocardial infarction (MI) or stroke within 6 months before Screening.

4. Uncontrolled acute infection.

5. Hematopoietic cell transplantation-comorbidity index (HCT-CI) > 6 points.

6. Concurrent malignant disease with the exception of treated basalioma/spinalioma of the skin or early-stage cervix carcinoma, or early-stage prostate cancer. Previous treatment for other malignancies (not listed above) must have been terminated at least 24 months before registration and no evidence of active disease shall be documented since then.

7. Major coagulopathy or bleeding disorder.

8. Other serious medical condition that could potentially interfere with the completion of treatment according to this protocol or that would impair tolerance to therapy or prolong hematological recovery.

9. Lack of cooperation to allow study treatment as outlined in this protocol.

10. Pregnancy or lactating female participants.

11. The use of any anti-cancer investigational agents within 21 days prior to the expected start of trial treatment and interval of 14 days to last administration of salvage treatment.

12. Receiving treatment with drugs known to prolong the QT/QTc interval.

13. QTc interval (Fridericia's formula) > 450 millisecond (msec), based on the mean of triplicate Screening 12-lead electrocardiograms (ECGs).

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Mundipharma-EDO GmbH

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Parameswaran Hari, MD

Role: STUDY_CHAIR

Study Chair

Dagmar Hess

Role: STUDY_CHAIR

2nd Study Chair

Locations

University of Alabama

Birmingham, Alabama, United States

University of Kansas Medical Center Kansas City

Kansas City, Kansas, United States

Memorial Sloan Kettering Cancer Centre

New York, New York, United States

Carolinas Healthcare System

Charlotte, North Carolina, United States

Vanderbilt-Ingram Cancer Center

Nashville, Tennessee, United States

University of Texas MD Anderson Cancer Center

Houston, Texas, United States

Froedtert & Medical College of Wisconsin, Cancer Center - Froedtert Hospital

Milwaukee, Wisconsin, United States

Oslo Myeloma Center, Oslo University Hospital

Oslo, , Norway

Universitatsspital Basel

Basel, , Switzerland

Universitatsspital Bern

Bern, , Switzerland

Department of Clinical Research Oncology/Hematology, Kantonsspital St. Gallen

Sankt Gallen, , Switzerland

University Hospital Zurich

Zurich, , Switzerland

Countries

United States; Norway; Switzerland

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2018-001907-35

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

EDO-S101-1004

Identifier Type: -

Identifier Source: org_study_id