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

NCT ID: NCT01862328

Last Updated: 2020-06-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 64 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-06-10
• Study Completion Date: 2018-05-21

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

Study Design

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

Study Groups

MLN4924 and Docetaxel (Arm 1)

Group Type: EXPERIMENTAL

MLN4924

Intervention Type: DRUG

MLN4924 (intravenously [IV]) in participants in a 21-day cycle:

• MLN4924 on Days 1,3,5 of each cycle

Docetaxel

Intervention Type: DRUG

Docetaxel (IV) in participants in a 21-day cycle:

• Docetaxel on Day 1 of each cycle

MLN4924 + Paclitaxel + Carboplatin (Arm 2)

Group Type: EXPERIMENTAL

MLN4924

Intervention Type: DRUG

MLN4924 (intravenously [IV]) in participants in a 21-day cycle:

• MLN4924 on Days 1,3,5 of each cycle

Paclitaxel

Intervention Type: DRUG

Paclitaxel (IV) in a 21-day cycle:

• Paclitaxel on Day 1 of each cycle

Carboplatin

Intervention Type: DRUG

Carboplatin (IV) in participants in a 21-day cycle:

• Carboplatin on Day 1 of each cycle

MLN4924 + Gemcitabine (Arm 3)

Group Type: EXPERIMENTAL

MLN4924

Intervention Type: DRUG

MLN4924 (intravenously [IV]) in participants in a 21-day cycle:

• MLN4924 on Days 1,3,5 of each cycle

Gemcitabine

Intervention Type: DRUG

Gemcitabine (IV) in participants in a 28-day cycle:

-Gemcitabine on Days 1,8,15 of each cycle

Interventions

MLN4924

MLN4924 (intravenously [IV]) in participants in a 21-day cycle:

• MLN4924 on Days 1,3,5 of each cycle

Intervention Type: DRUG

Paclitaxel

Paclitaxel (IV) in a 21-day cycle:

• Paclitaxel on Day 1 of each cycle

Intervention Type: DRUG

Gemcitabine

Gemcitabine (IV) in participants in a 28-day cycle:

-Gemcitabine on Days 1,8,15 of each cycle

Intervention Type: DRUG

Docetaxel

Docetaxel (IV) in participants in a 21-day cycle:

• Docetaxel on Day 1 of each cycle

Intervention Type: DRUG

Carboplatin

Carboplatin (IV) in participants in a 21-day cycle:

• Carboplatin on Day 1 of each cycle

Intervention Type: DRUG

Other Intervention Names

Pevonedistat

Eligibility Criteria

Inclusion Criteria

1. 18 years of age or older

2. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1

3. 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

4. Recovered (that is, <=Grade 1 toxicity) from the effects of prior antineoplastic therapy

5. Female participants who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception or agree to practice true abstinence

6. Male participants who agree to practice effective barrier contraception or agree to practice true abstinence

7. Voluntary written consent must be given before performance of any study-related procedure

8. Suitable venous access for the study-required blood sampling

9. Adequate clinical laboratory values during the screening period as specified in the protocol

10. 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

11. 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

Exclusion Criteria

1. Major surgery within 14 days before the first dose of study drug

2. Female participants who are lactating or pregnant

3. Active uncontrolled infection or severe infectious disease

4. Receiving antibiotic therapy within 14 days before the first dose of study treatment

5. Life-threatening illness unrelated to cancer

6. Known hypersensitivity to study-assigned chemotherapy

7. Prior treatment with MLN4924; however, prior treatment with docetaxel, paclitaxel,carboplatin, and gemcitabine is allowed

8. 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

9. Persistent diarrhea (greater than Grade 2) lasting >3 days within 2 weeks before the first dose of study treatment

10. Systemic antineoplastic therapy within 21 days before the first dose of study drug

11. Radiotherapy within 14 days preceding the first dose of study treatment

12. Prior treatment with radiation therapy involving greater than or equal to (>=) 25% of the hematopoietically active bone marrow

13. 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

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

Sponsors

Millennium Pharmaceuticals, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Monitor

Role: STUDY_DIRECTOR

Millennium Pharmaceuticals, Inc.

Locations

Atlanta, Georgia, United States

St Louis, Missouri, United States

Chapel Hill, North Carolina, United States

Cleveland, Ohio, United States

Philadelphia, Pennsylvania, United States

Nashville, Tennessee, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 31355467 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 29781056 (View on PubMed)

Provided Documents

Document Type: Statistical Analysis Plan

View Document

Document Type: Study Protocol

View Document

Other Identifiers

U1111-1220-1470

Identifier Type: OTHER

Identifier Source: secondary_id

C15010

Identifier Type: -

Identifier Source: org_study_id