Clinical trial NCT03687125: Tinostamustine Conditioning and Autologous Stem Cell
Official title: Phase 1/2 Open-label Trial of Tinostamustine Conditioning and Autologous Stem Cell Transplantation for Salvage Treatment in Relapsed / Refractory Multiple Myeloma (TITANIUM 1)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Multiple Myeloma in Relapse
Multiple Myeloma Progression
Multiple Myeloma With Failed Remission
Lead sponsor: Mundipharma-EDO GmbH
Sponsor class: INDUSTRY
First posted: 2018-09-27
Enrollment: 6
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Phase 1 Does escalation followed by Phase 2 Expansion at MTD
Primary purpose: TREATMENT

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.

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).

Primary outcomes:
measure: Phase 2: Objective Response Rate (ORR) Based on International Myeloma Working Group (IMWG) Response Criteria
timeFrame: at Day 100 post-autologous stem cell transplant (ASCT)
measure: Phase 1: Number of Participants With Dose Limiting Toxicities (DLT)
timeFrame: Phase 1: From Day -1 up to 30 Days post-ASCT
Secondary outcomes:
measure: Phase 1 and 2: Objective Response Rate (ORR) for Participants Treated at the Recommended Phase 2 Dose (RP2D)
timeFrame: at Day 100 post ASCT
measure: Phase 1 and 2: Number of Participants With Neutrophil and Platelet Engraftment Failure
timeFrame: up to 6 months
measure: Phase 1 and 2: Duration of Cytopenia
timeFrame: Up to 6 months
measure: Phase 1 and 2: Number of Participants With Treatment Related Mortality (TRM)
timeFrame: Up to 6 months
measure: Phase 1 and 2: Number of Participants With Transplant-related Non-hematologic Grade 3 Toxicity
timeFrame: Up to 6 months
measure: Phase 1 and 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
timeFrame: From first dose of tinostamustine up to end of study (up to 6 months)
measure: Phase 1 and 2: Change From Baseline in Hematology Parameters
timeFrame: Baseline (Day -1), Day 30
measure: Phase 1 and 2: Change From Baseline in Clinical Serum Chemistry Tests: Electrolytes
timeFrame: Baseline (Day -1), Day 100
measure: Phase 1 and 2: Change From Baseline in Clinical Serum Chemistry Tests: Liver Function Parameters
timeFrame: Baseline (Day -1), Day 100
measure: Phase 1 and 2: Change From Baseline in Clinical Serum Chemistry Tests: Renal Function Parameters
timeFrame: Baseline (Day -1), Day 100
measure: Phase 1 and 2: Change From Baseline in Clinical Serum Chemistry Tests: Total Protein
timeFrame: Baseline (Day -1), Day 100
measure: Phase 1 and 2: Time to Reach Maximum Plasma Concentration (Tmax) of Tinostamustine and Its Metabolites
timeFrame: Pre-infusion, 0.50, 0.75, 1, 3, 6, 24, 48 hours post-infusion
measure: Phase 1 and 2: Maximum Observed Plasma Concentration (Cmax) of Tinostamustine and Its Metabolites
timeFrame: Pre-infusion, 0.50, 0.75, 1, 3, 6, 24, 48 hours post-infusion
measure: Phase 1 and 2: Area Under the Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUC0-t) of Tinostamustine and Its Metabolites
timeFrame: Pre-infusion, 0.50, 0.75, 1, 3, 6, 24, 48 hours post-infusion
measure: Phase 1 and 2: Area Under the Concentration-time Curve From Time Zero to 12 Hours (AUC0-12h) of Tinostamustine and Its Metabolites
timeFrame: Pre-infusion, 0.50, 0.75, 1, 3, 6 hours post-infusion
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama
state: Alabama
city: Kansas City
country: United States
facility: University of Kansas Medical Center Kansas City
state: Kansas
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Centre
state: New York
city: Charlotte
country: United States
facility: Carolinas Healthcare System
state: North Carolina
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: Milwaukee
country: United States
facility: Froedtert & Medical College of Wisconsin, Cancer Center - Froedtert Hospital
state: Wisconsin
city: Oslo
country: Norway
facility: Oslo Myeloma Center, Oslo University Hospital
city: Basel
country: Switzerland
facility: Universitatsspital Basel
city: Bern
country: Switzerland
facility: Universitatsspital Bern
city: Saint Gallen
country: Switzerland
facility: Department of Clinical Research Oncology/Hematology, Kantonsspital St. Gallen
city: Zürich
country: Switzerland
facility: University Hospital Zurich
Study officials:
affiliation: Study Chair
name: Parameswaran Hari, MD
role: STUDY_CHAIR
affiliation: 2nd Study Chair
name: Dagmar Hess
role: STUDY_CHAIR
References: