Tinostamustine Conditioning and Autologous Stem Cell

NCT03687125 | Terminated Phase 1 Results DMC FDA Drug

• 2 other identifiers: EDO-S101-10042018-001907-35
• Study Type: interventional
• Target: 6
• Locations: 3 countries
• Sites: 12

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.

Conditions

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

Outcome Measures

Primary Outcomes (2)

• Phase 2: Objective Response Rate (ORR) Based on International Myeloma Working Group (IMWG) Response Criteria

  ORR was defined as the participants with a complete response (CR) or very good partial response (VGPR) or partial response (PR) as determined by IMWG Response Criteria. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (target/non target) must have reduction in short axis to less than (\<) 10 mm; PR was defined as at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum longest diameter; VGPR was defined as a \>90% reduction in serum IgM levels from baseline.

  at Day 100 post-autologous stem cell transplant (ASCT)

• Phase 1: Number of Participants With Dose Limiting Toxicities (DLT)

  DLT was defined as at least possibly related to tinostamustine based on common terminology criteria for adverse events 4.03 (CTCAE 4.03): (1) delayed engraftment (greater than \[\>\] 30 days after ASCT) where subject has not met criteria for both neutrophil (first of 3 consecutive days with ANC \> 0.5×10\^9/liter \[L\]) and platelet (plt) engraftment (first of 3 consecutive days of plt count \> 20×10\^9/L without plt transfusion in prior 7 days) (2) QTcF \> 500 millisecond (msec) or \> 60 msec increase from baseline with duration of \> 30 minutes or greater than or equal to (\>=) Grade 3 QTcF interval prolongation with ventricular arrhythmia (3) Grade 4 non-hematologic toxicity (4) Grade 3 non-hematologic toxicity related to treatment, except: nausea, emesis, diarrhea, fatigue, dehydration, glucose intolerance, skin rash with treatment, fever (\> 40C for \>= 24 hours), infection, dyspnea, hypoxia, pneumonitis, pain, dysphagia, oral mucositis, anorexia, flu-like or engraftment syndrome, weight.

  Phase 1: From Day -1 up to 30 Days post-ASCT

Secondary Outcomes (15)

• Phase 1 and 2: Objective Response Rate (ORR) for Participants Treated at the Recommended Phase 2 Dose (RP2D)

  at Day 100 post ASCT

• Phase 1 and 2: Number of Participants With Neutrophil and Platelet Engraftment Failure

  up to 6 months

• Phase 1 and 2: Duration of Cytopenia

  Up to 6 months

• Phase 1 and 2: Number of Participants With Treatment Related Mortality (TRM)

  Up to 6 months

• Phase 1 and 2: Number of Participants With Transplant-related Non-hematologic Grade 3 Toxicity

  Up to 6 months

Study Arms (2)

Tinostamustine 180 mg/m^2

EXPERIMENTAL

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.

Drug: Tinostamustine; Procedure: Autologous Stem Cell Transplant (ASCT)

Tinostamustine 220 mg/m^2

EXPERIMENTAL

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

Drug: Tinostamustine; Procedure: Autologous Stem Cell Transplant (ASCT)

Interventions

Tinostamustine DRUG

Participants received tinostamustine IV injection.

Tinostamustine 180 mg/m^2; Tinostamustine 220 mg/m^2

Autologous Stem Cell Transplant (ASCT) PROCEDURE

Undergo autologous stem cell transplant

Tinostamustine 180 mg/m^2; Tinostamustine 220 mg/m^2

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.
• 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.)
• 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.)
• Age 18-75 years.
• Eastern Cooperative Oncology Group (ECOG) performance status score lesser than (\<) 3 at Screening.
• Creatinine clearance \>= 40 milliliter per minute (mL/min), as determined by a local laboratory using the Cockcroft-Gault equation within 28 days before ASCT.
• Left ventricular ejection fraction (LVEF) \>= 40 percent (%) within 28 days before ASCT.
• 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.
• 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.
• Potassium within the local laboratory's normal range. (Potassium supplementation is permissible.)

You may not qualify if:

• Participants meeting any of the following criteria are not eligible for study entry:
• History of central nervous system (CNS) disease involvement.
• Primary or secondary plasma cell leukemia at any time point prior to transplant.
• Myocardial infarction (MI) or stroke within 6 months before Screening.
• Uncontrolled acute infection.
• Hematopoietic cell transplantation-comorbidity index (HCT-CI) \> 6 points.
• 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.
• Major coagulopathy or bleeding disorder.
• 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.
• Lack of cooperation to allow study treatment as outlined in this protocol.
• Pregnancy or lactating female participants.
• 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.
• Receiving treatment with drugs known to prolong the QT/QTc interval.
• QTc interval (Fridericia's formula) \> 450 millisecond (msec), based on the mean of triplicate Screening 12-lead electrocardiograms (ECGs).

Sponsors & Collaborators

• Mundipharma-EDO GmbH: lead

Study Sites (12)

University of Alabama

Birmingham, Alabama, 35294, United States

Location

University of Kansas Medical Center Kansas City

Kansas City, Kansas, 66160, United States

Location

Memorial Sloan Kettering Cancer Centre

New York, New York, 10065, United States

Location

Carolinas Healthcare System

Charlotte, North Carolina, 28204, United States

Location

Vanderbilt-Ingram Cancer Center

Nashville, Tennessee, 37203, United States

Location

University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

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

Milwaukee, Wisconsin, 53226, United States

Location

Oslo Myeloma Center, Oslo University Hospital

Oslo, Norway

Location

Universitatsspital Basel

Basel, Switzerland

Location

Universitatsspital Bern

Bern, Switzerland

Location

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

Sankt Gallen, Switzerland

Location

University Hospital Zurich

Zurich, Switzerland

Location

MeSH Terms

Interventions

tinostamustine

Limitations and Caveats

Study was early terminated during Phase 1 due to sponsor decision on 17 April 2019 (adverse events limited administration of higher doses required to achieve myeloablative conditioning necessary in this population). Hence, no participants were enrolled in Phase 2 and efficacy analysis were not performed in the both Phase 1 and 2.

Results Point of Contact

• Title: Terry Nichols
• Organization: Mundipharma Research Limited

terry.nichols@mundipharma-rd.eu

(0044)1223424444

Study Officials

• Parameswaran Hari, MD

  Study Chair

  STUDY CHAIR

• Dagmar Hess

  2nd Study Chair

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Phase 1 Does escalation followed by Phase 2 Expansion at MTD

Study Record Dates

• First Submitted: August 29, 2018
• First Posted: September 27, 2018
• Study Start: October 15, 2018
• Primary Completion: April 17, 2019
• Study Completion: April 17, 2019
• Last Updated: June 18, 2021
• Results First Posted: June 18, 2021

Record last verified: 2021-05

Locations

NO (1); CH (4); US (7)