Clinical trial NCT01862328: Dose Escalation, Multi-arm Study of MLN4924 Plus Docetaxel, Gemcitabine, or Combination of Carboplatin and Paclitaxel in Participants With Solid Tumors
Official title: A Phase 1b, Open-Label, Dose Escalation, Multi-arm Study of MLN4924 Plus Docetaxel, Gemcitabine, or Combination of Carboplatin and Paclitaxel in Patients With Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Solid Tumors
Keywords: MLN4924
Solid Tumors
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2013-05-24
Enrollment: 64
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: OTHER

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.


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

Primary outcomes:
measure: Number of Participants Who Experience at Least 1 Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
timeFrame: Baseline up to 30 days after the last dose of study drug (up to 5 years)
measure: Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings
timeFrame: Baseline up to 30 days after the last dose of study drug (up to 5 years)
measure: Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings
timeFrame: Baseline up to 30 days after the last dose of study drug (up to 5 years)
Secondary outcomes:
measure: Percentage of Participants With Objective Response
timeFrame: 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])
measure: Duration of Response
timeFrame: 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)
measure: Dose-escalation Phase: Plasma Concentrations-time Data of MLN4924
timeFrame: 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])
measure: MTD Expansion Phase: Plasma Concentrations-time Data of MLN4924
timeFrame: 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])
Other outcomes:
Locations:
city: Atlanta
country: United States
state: Georgia
city: Saint Louis
country: United States
state: Missouri
city: Chapel Hill
country: United States
state: North Carolina
city: Cleveland
country: United States
state: Ohio
city: Philadelphia
country: United States
state: Pennsylvania
city: Nashville
country: United States
state: Tennessee
Study officials:
affiliation: Millennium Pharmaceuticals, Inc.
name: Medical Monitor
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.