Dose Escalation, Multi-arm Study of MLN4924 Plus Docetaxel, Gemcitabine, or Combination of Carboplatin and Paclitaxel in Participants With Solid Tumors

NCT01862328 | Completed Phase 1 Results

• 2 other identifiers: C15010U1111-1220-1470
• Study Type: interventional
• Target: 64
• Locations: 1 country
• Sites: 6

Brief Summary

The purpose of this study is to establish the maximum tolerated dose (MTD) and assess the safety and tolerability of MLN4924 (pevonedistat) in combination with docetaxel, paclitaxel and carboplatin, and gemcitabine in participants with solid tumors.

Conditions

Solid Tumors

Keywords

MLN4924; Solid Tumors

Outcome Measures

Primary Outcomes (3)

• Number of Participants Who Experience at Least 1 Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

  Baseline up to 30 days after the last dose of study drug (up to 5 years)

• Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings

  Baseline up to 30 days after the last dose of study drug (up to 5 years)

• Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings

  Baseline up to 30 days after the last dose of study drug (up to 5 years)

Secondary Outcomes (4)

• Percentage of Participants With Objective Response

  Screening, Cycle 2 Days 15 (Arm 1, 2a, and 2) and 22 (Arm 3) then every other Cycle thereafter up to 30 days after the last dose of study drug (up to 5 years) (Cycle Length = 21 days [Arm 1, 2a, and 2] and 28 days [Arm 3])

• Duration of Response

  From the date of first documented response (CR or PR) to the date of first documented PD or the date of last disease assessment if the participants discontinued the study before PD (up to 5 years)

• Dose-escalation Phase: Plasma Concentrations-time Data of MLN4924

  Cycle 1 Day 1 pre-dose and at multiple time points (up to 20 hours) post-dose (Cycle Length=21 days [Arm 1 and 2] and 28 days [Arm 3])

• MTD Expansion Phase: Plasma Concentrations-time Data of MLN4924

  Cycle 1 Days 1 and 5 pre-dose and at multiple time points (up to 20 hours) post-dose (Cycle Length=21 days [Arm 1 and 2])

Study Arms (3)

MLN4924 and Docetaxel (Arm 1)

EXPERIMENTAL

Drug: MLN4924; Drug: Docetaxel

MLN4924 + Paclitaxel + Carboplatin (Arm 2)

EXPERIMENTAL

Drug: MLN4924; Drug: Paclitaxel; Drug: Carboplatin

MLN4924 + Gemcitabine (Arm 3)

EXPERIMENTAL

Drug: MLN4924; Drug: Gemcitabine

Interventions

MLN4924 DRUG

MLN4924 (intravenously \[IV\]) in participants in a 21-day cycle: * MLN4924 on Days 1,3,5 of each cycle

Also known as: Pevonedistat

MLN4924 + Gemcitabine (Arm 3); MLN4924 + Paclitaxel + Carboplatin (Arm 2); MLN4924 and Docetaxel (Arm 1)

Paclitaxel DRUG

Paclitaxel (IV) in a 21-day cycle: * Paclitaxel on Day 1 of each cycle

MLN4924 + Paclitaxel + Carboplatin (Arm 2)

Gemcitabine DRUG

Gemcitabine (IV) in participants in a 28-day cycle: -Gemcitabine on Days 1,8,15 of each cycle

MLN4924 + Gemcitabine (Arm 3)

Docetaxel DRUG

Docetaxel (IV) in participants in a 21-day cycle: \- Docetaxel on Day 1 of each cycle

MLN4924 and Docetaxel (Arm 1)

Carboplatin DRUG

Carboplatin (IV) in participants in a 21-day cycle: \- Carboplatin on Day 1 of each cycle

MLN4924 + Paclitaxel + Carboplatin (Arm 2)

Eligibility Criteria

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

You may qualify if:

• years of age or older
• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1
• Have a histologically or cytologically confirmed metastatic or locally advanced and incurable solid tumor that is felt to be appropriate for treatment with 1 of the 3 chemotherapy regimens in this study, or have progressed despite standard therapy, or for whom conventional therapy is not considered effective. The tumor must be radiographically or clinically evaluable and/or measurable
• Recovered (that is, \<=Grade 1 toxicity) from the effects of prior antineoplastic therapy
• Female participants who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception or agree to practice true abstinence
• Male participants who agree to practice effective barrier contraception or agree to practice true abstinence
• Voluntary written consent must be given before performance of any study-related procedure
• Suitable venous access for the study-required blood sampling
• Adequate clinical laboratory values during the screening period as specified in the protocol
• Participants who are willing to refrain from donating blood for at least 90 days after their final dose of MLN4924 and (for male participants) willing to refrain from donating semen for at least 4 months after their final dose of MLN4924
• Availability of fixed tumor specimen (block or slides) for exploratory biomarker analysis. If no slides or block are available, fresh tumor biopsies should be obtained and used for these assessments

You may not qualify if:

• Major surgery within 14 days before the first dose of study drug
• Female participants who are lactating or pregnant
• Active uncontrolled infection or severe infectious disease
• Receiving antibiotic therapy within 14 days before the first dose of study treatment
• Life-threatening illness unrelated to cancer
• Known hypersensitivity to study-assigned chemotherapy
• Prior treatment with MLN4924; however, prior treatment with docetaxel, paclitaxel,carboplatin, and gemcitabine is allowed
• History of severe hypersensitivity reactions to docetaxel (polysorbate 80-based formulations) for participants to be enrolled in Arm 1 (MLN4924 + docetaxel), history of hypersensitivity to carboplatin for participants to be enrolled in Arm 2 (MLN4924 + paclitaxel + carboplatin), or history of severe hypersensitivity to paclitaxel (cremophor-based formulations) for participants to be enrolled in Arm 2
• Persistent diarrhea (greater than Grade 2) lasting \>3 days within 2 weeks before the first dose of study treatment
• Systemic antineoplastic therapy within 21 days before the first dose of study drug
• Radiotherapy within 14 days preceding the first dose of study treatment
• Prior treatment with radiation therapy involving greater than or equal to (\>=) 25% of the hematopoietically active bone marrow
• Treatment with cytochrome P450 3A (CYP3A) inducers within 14 days before the first dose of MLN4924.
• Treatment with CYP3A inhibitors within 14 days before the first dose of MLN4924; however, voriconazole and fluconazole need only be stopped for 3 days before MLN4924. Participants must have no history of amiodarone use in the 6 months before the first dose of MLN4924 14. Clinically uncontrolled central nervous system (CNS) involvement 15. Any serious medical or psychiatric illness 16. Treatment with any investigational products 21 days prior to treatment 17. Unwilling or unable to refrain from using statins 24 hours before, the day of, and 24 hours after each MLN4924 administration 18. Known human immunodeficiency virus (HIV) positive or hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection 19. Known hepatic cirrhosis 20. Known cardiac/cardiopulmonary disease 21. Left ventricular ejection fraction 23. with a cardiac pacer whose heart rate is set at a fixed rate and participants on concomitant medication that may limit increase in heart rate in response to hypotension 24 History of severe intolerance to cytotoxic agent(s) given in the assigned arm

Sponsors & Collaborators

• Millennium Pharmaceuticals, Inc.: lead

Study Sites (6)

Unknown Facility

Atlanta, Georgia, 30322, United States

Location

Unknown Facility

St Louis, Missouri, 63110, United States

Location

Unknown Facility

Chapel Hill, North Carolina, 27599, United States

Location

Unknown Facility

Cleveland, Ohio, 44106-4948, United States

Location

Unknown Facility

Philadelphia, Pennsylvania, 19104, United States

Location

Unknown Facility

Nashville, Tennessee, 37203, United States

Location

Related Publications (2)

• Faessel HM, Mould DR, Zhou X, Faller DV, Sedarati F, Venkatakrishnan K. Population pharmacokinetics of pevonedistat alone or in combination with standard of care in patients with solid tumours or haematological malignancies. Br J Clin Pharmacol. 2019 Nov;85(11):2568-2579. doi: 10.1111/bcp.14078. Epub 2019 Sep 4.

  PMID: 31355467 DERIVED

• Lockhart AC, Bauer TM, Aggarwal C, Lee CB, Harvey RD, Cohen RB, Sedarati F, Nip TK, Faessel H, Dash AB, Dezube BJ, Faller DV, Dowlati A. Phase Ib study of pevonedistat, a NEDD8-activating enzyme inhibitor, in combination with docetaxel, carboplatin and paclitaxel, or gemcitabine, in patients with advanced solid tumors. Invest New Drugs. 2019 Feb;37(1):87-97. doi: 10.1007/s10637-018-0610-0. Epub 2018 May 21.

  PMID: 29781056 DERIVED

MeSH Terms

Interventions

pevonedistat; Paclitaxel; Gemcitabine; Docetaxel; Carboplatin

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Coordination Complexes

Results Point of Contact

• Title: Medical Director
• Organization: Takeda

trialdisclosures@takeda.com

+1-877-825-3327

Study Officials

• Medical Monitor

  Millennium Pharmaceuticals, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

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

Study Record Dates

• First Submitted: May 15, 2013
• First Posted: May 24, 2013
• Study Start: June 10, 2013
• Primary Completion: May 21, 2018
• Study Completion: May 21, 2018
• Last Updated: June 22, 2020
• Results First Posted: June 22, 2020

Record last verified: 2020-06

Data Sharing

• IPD Sharing: Will share

Locations

US (6)