Symptoms and General Pathology

All Conditions

Neoplasms

Blood and Lymph Conditions

Immune System Diseases

Behaviors and Mental Disorders

Rare Diseases

Recurrence

Lymphoma

Lymphoma, T-Cell

Lymphoma, Mantle-Cell

Aggression

Lymphoma, Non-Hodgkin

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphosarcoma

Mantle Cell Lymphoma

Antineoplastic Agents

All Drugs and Chemicals

Nivolumab

Veliparib

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

Patients receive veliparib PO BID on day 1 and nivolumab IV over 30 minutes on days 1 and 15 of courses 1-4 and IV over 60 minutes on day 1 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis

Pharmacological Study

Young K. Chae, MD, MPH, MBA

The purpose of this research study is to determine the highest and safest dose of the experimental drug veliparib when combined with nivolumab. We will also study how safely this combination of medication can be given in advanced cancer and lymphoma and benefits of receiving this therapy. Nivolumab is currently approved in certain cancers such as melanoma, lung cancer and kidney cancer. Veliparib is not yet approved for use in the United States, and is considered experimental. Veliparib inhibits (blocks) the activity of the enzyme PARP. This blocking activity may prevent the cancer cell from repairing itself and resume growing. Nivolumab increases T cells in your immune system, which allows your immune system to attack the cancer. We think the combination of these drugs will be more effective against your cancer.

PRIMARY OBJECTIVES:

I. To identify maximum tolerated dose (MTD) for the combination treatment of nivolumab and veliparib in patients with advanced refractory solid cancers and lymphoma.

SECONDARY OBJECTIVES:

I. To evaluate the safety and tolerability of nivolumab and veliparib in patients with advanced refractory solid cancers and lymphoma with and without mutations in selected DNA repair genes.

II. To evaluate the efficacy of treatment with nivolumab and veliparib in this population by objective response rate (ORR, defined as partial response \[PR\] + complete response \[CR\]), clinical benefit rate (CBR, defined as stable disease \[SD\] for \>= 12 weeks, PR, + CR), and progression free survival (PFS, defined as the time from treatment initiation to documented disease progression) using Response Evaluation Criteria in Solid Tumors (RECIST) criteria version (v)1.1 or Lugano criteria.

III. To evaluate efficacy of treatment with nivolumab and veliparib in this population by ORR, CBR, and immune-related PFS (irPFS) using irRECIST criteria.

IV. To evaluate overall survival (OS) in this population at 3 years from the start of treatment.

V. To evaluate the proportion of patients alive and progression free at 24 weeks in this population.

VI. To evaluate ORR to nivolumab and veliparib in patients with prior exposure to single agent PD-1/PD-L1 inhibitors.

TERTIARY OBJECTIVES:

I. To evaluate if any of the following predict response to veliparib in combination with nivolumab: tissue PD-L1 protein expression, immune cell infiltration markers.

II. To demonstrate the pharmacodynamic effects of veliparib and nivolumab on biomarkers including PD-L1, TILs, T cell subpopulations, and T cell receptor genotype.

III. To explore the pattern of clonal changes through circulating cell free DNA assay.

IV. To assess the dynamic change in both immune and genomic biomarkers in blood that may correlate with response to veliparib.

OUTLINE: This is a dose-escalation study of veliparib.

Patients receive veliparib orally (PO) twice daily (BID) on day 1 and nivolumab intravenously (IV) over 30 minutes on days 1 and 15 of courses 1-4 and IV over 60 minutes on day 1 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 3, 6, 9, and 12 months and then every 6 months for 3 years.

Nivolumab and Veliparib in Treating Patients With Recurrent or Refractory Stage IV Solid Tumors That Cannot Be Removed by Surgery or Lymphoma With or Without Alterations in DNA Repair Genes

Phase I/Ib Study of Nivolumab and Veliparib in Patients With Advanced Solid Tumors and Lymphoma With and Without Alterations in Selected DNA Repair Genes

The MTD will be defined as the highest dose that causes dose-limiting toxicities (DLTs) in \<2 of 6 patients. Toxicity will be assessed using CTCAEv4.03. A DLT is defined as an Adverse Event (AE) or abnormal laboratory value assessed as at least possibly related to the study medication, occurs ≤ 28 days (1 cycle) following the first dose of veliparib and nivolumab and meets any of the following criteria:

Grade ≥ 3 non-hematologic toxicities that represent at least a 2-grade increase from baseline excluding Nausea, vomiting, diarrhea lasting ≤48 hours, Electrolyte abnormalities resolving within ≤24 hours, Hypersensitivity reactions,and Alopecia.

Grade 4 thrombocytopenia (platelets \< 25.0 x 109 /L) Grade 3 thrombocytopenia with bleeding (platelets \< 0.5 x 109 /L) 5. Grade 3 febrile neutropenia with fever lasting for \> 7 days 6. Grade 4 febrile neutropenia of any duration 7. Dosing delay due to toxicity for \> 14 consecutive days from the date nivolumab or veliparib is due.

Evaluate the safety and tolerability of nivolumab and veliparib by assessing the number, frequency, and severity of adverse events as defined by the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

Overall response rate or ORR, (partial response (PR) + complete response (CR)) will be evaluated using RECIST criteria v1.1 or Lugano 2014 classification for assessment of Lymphoma.

Per RECIST v. 1.1: PR= : At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. CR= Disappearance of all target lesions.

Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm.

Per Lugano 2014 classification, scored on a Deauville 5-point scale (an internationally-recommended scale using FDG PET-CT in the initial staging and assessment of treatment response in Hodgkin lymphoma (HL) and certain types of non-Hodgkin lymphomas (NHL).

* Partial metabolic response (PMR): score of 4 or 5 with reduced uptake compared with baseline and residual mass(es) of any size.
* Complete metabolic response (CMR): Score of 1, 2 or 3 in nodal or extranodal sites with or without a residual mass

CBR= stable disease for ≥12 weeks + Partial Response + Complete Response per RECIST v1.1 for solid tumors or Lugano 2014 classification for lymphomas. Lugano scored on a Deauville 5-point scale. RECIST v. 1.1: PR= : At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. CR= Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. SD=Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study. Lugano 2014 classification: PR: score of 4 or 5 with reduced uptake compared with baseline and residual mass(es) of any size. CR: Score of 1, 2 or 3 in nodal or extranodal sites with or without a residual mass. SD: No metabolic response, Score 4 or 5 with no significant change in FDG uptake from baseline at interim or end of treatment.

To evaluate Progression Free Survival (PFS) for patients treated with nivolumab and veliparib, defined as the time from treatment initiation to documented disease progression. Evaluated by RECIST criteria v1.1 for solid tumors or Lugano 2014 classification for assessment of Lymphoma. RECIST v. 1.1 definition for PD (Progressive disease): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Lugano 2014 classification, scored on a Deauville 5-point scale (an internationally-recommended scale using FDG PET-CT in the initial staging and assessment of treatment response in Hodgkin lymphoma (HL) and certain types of non-Hodgkin lymphomas (NHL). Per Lugano criteria: Partial metabolic disease (PMD):Score 4 or 5 with an increase in intensity of uptake from baseline and/or new FDG-avid foci consistent with lymphoma at interim or end-of-treatment assessment.

Overall Survival is defined as the time from treatment initiation until death due to any cause, assessed up to 3 years from the start of treatment.

To evaluate the number of patients alive and progression free at 24 weeks. -Per RECIST v. 1.1 (for solid tumors) progression is defined as : At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression.) -Lugano 2014 classification, scored on a Deauville 5-point scale (an internationally-recommended scale using FDG PET-CT in the initial staging and assessment of treatment response i Hodgkin lymphoma (HL) and certain types of non-Hodgkin lymphomas (NHL). Per Lugano criteria: Partial metabolic disease (PMD):Score 4 or 5 with an increase in intensity of uptake from baseline and/or new FDG-avid foci consistent with lymphoma at interim or end-of-treatment assessment.

Bristol-Myers Squibb

AbbVie

National Cancer Institute (NCI)

Northwestern University

Principal Investigator

The starting dose was Cohort level 1. There were no dose-limiting toxicities on Cohort 1 so the dose was never de-escalated, Cohort -1 never opened to enrollment.

Patients receive veliparib 200 mg (oral medication) twice daily and nivolumab IV over 30 minutes on days 1 and 15 of courses 1-4 and IV over 60 minutes on day 1 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis: Correlative studies

Nivolumab: Given IV

Pharmacological Study: Correlative studies

Veliparib: Given PO

Phase 1:Cohort-1 (Velaparib 200 mg PO Twice Daily + Nivolumab)

Patients receive veliparib 300 mg (oral medication) twice daily and nivolumab IV over 30 minutes on days 1 and 15 of courses 1-4 and IV over 60 minutes on day 1 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis: Correlative studies

Nivolumab: Given IV

Pharmacological Study: Correlative studies

Veliparib: Given PO

Phase 1:Cohort 1 (Velaparib 300 mg PO Twice Daily + Nivolumab)

Patients receive veliparib 400 mg (oral medication) twice daily and nivolumab IV over 30 minutes on days 1 and 15 of courses 1-4 and IV over 60 minutes on day 1 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis: Correlative studies

Nivolumab: Given IV

Pharmacological Study: Correlative studies

Veliparib: Given PO

Phase 1:Cohort 2 (Velaparib 400 mg PO Twice Daily + Nivolumab)

Phase 2 MTD: Velaparib 400 mg PO Twice Daily + Nivolumab

Velaparib (oral medication) twice daily and nivolumab IV over 30 minutes on days 1 and 15 of courses 1-4 and IV over 60 minutes on day 1 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

* Velaparib dose in Phase 1: Cohort -1: 200mg
* Nivolumab dose: Cycle 1-4: 240 mg IV every 14 days (Days 1 \& 15) + Cycle 5+: 480mg IV every 28 days (Day 1)

Laboratory Biomarker Analysis: Correlative studies

Nivolumab: Given IV

Pharmacological Study: Correlative studies

Veliparib: Given PO

Velaparib PO Twice Daily + Nivolumab (Cohort -1)

Velaparib (oral medication) twice daily and nivolumab IV over 30 minutes on days 1 and 15 of courses 1-4 and IV over 60 minutes on day 1 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

* Velaparib dose in Phase 1: Cohort 1: 300 mg,
* Nivolumab dose: Cycle 1-4: 240 mg IV every 14 days (Days 1 \& 15) + Cycle 5+: 480mg IV every 28 days (Day 1)

Laboratory Biomarker Analysis: Correlative studies

Nivolumab: Given IV

Pharmacological Study: Correlative studies

Veliparib: Given PO

Velaparib PO Twice Daily + Nivolumab (Cohort 1)

Velaparib (oral medication) twice daily and nivolumab IV over 30 minutes on days 1 and 15 of courses 1-4 and IV over 60 minutes on day 1 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

* Velaparib dose: 400 mg
* Nivolumab dose: Cycle 1-4: 240 mg IV every 14 days (Days 1 \& 15) + Cycle 5+: 480mg IV every 28 days (Day 1)

Laboratory Biomarker Analysis: Correlative studies

Nivolumab: Given IV

Pharmacological Study: Correlative studies

Veliparib: Given PO

Velaparib PO Twice Daily + Nivolumab (Cohort 2)

Patients in all Phase 1 cohorts and Phase 2 receive velaparib (oral medication) twice daily and nivolumab IV over 30 minutes on days 1 and 15 of courses 1-4 and IV over 60 minutes on day 1 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

* Velaparib dose 400 mg
* Nivolumab dose: Cycle 1-4: 240 mg IV every 14 days (Days 1 \& 15) + Cycle 5+: 480mg IV every 28 days (Day 1)

Laboratory Biomarker Analysis: Correlative studies

Nivolumab: Given IV

Pharmacological Study: Correlative studies

Veliparib: Given PO

Velaparib PO Twice Daily + Nivolumab (Phase 2)

Total

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Patients counted under "Yes" tested positive for a mutation in the following selected DNA repair genes (involved in cell cycle arrest signal transduction): BRCA1 pathway, Fanconi's proteins pathway, and RAD51 pathway: \[ATR, ATM, CHEK1, CHEK2, BRCA1, BRIP1, BAP1, BARD1, FANCD2, FANCE, FANCC, RAD50, FANCA, RAD51, BRCA2, PALB2, CDK12 (ENSG00000167258, also known as CRK7, CRKR, CRKRS), POLE, POLD1, BRAC2, PRKDC, ERCC2, POLQ, MRE11A, NBN (MBS1)\], or at least one gene amplification in FANCD2, FANCE, FANCC, FANCA, C11orf30 (EMSY).

Mutation in DNA repair gene present

Solid Tumor

Lymphoma vs Solid Tumor

The starting dose (Cohort 1) was never de-escalated, so Cohort -1 never opened.

The original accrual goal was 50 patients. Due to funding issues the accrual goal was reduced to 15 patients.

Young Kwang Chae, MD, MPH, MBA

Patients in all Phase 1 cohorts receive velaparib (oral medication) twice daily and nivolumab IV over 30 minutes on days 1 and 15 of courses 1-4 and IV over 60 minutes on day 1 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

\*Velaparib dose in Phase 1: Cohort -1: 200mg, Cohort 1: 300 mg, Cohort 2: 400 mg

Laboratory Biomarker Analysis: Correlative studies

Nivolumab: Given IV

Pharmacological Study: Correlative studies

Veliparib: Given PO

Velaparib PO Twice Daily + Nivolumab (Phase 1)

Maximum Tolerated Dose (MTD)

Incidence of Adverse Events

Complete Response

Partial Response

Velaparib (oral medication) twice daily and nivolumab IV over 30 minutes on days 1 and 15 of courses 1-4 and IV over 60 minutes on day 1 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

* Velaparib dose in Phase 1: Cohort 1: 300 mg
* Nivolumab dose: Cycle 1-4: 240 mg IV every 14 days (Days 1 \& 15) + Cycle 5+: 480mg IV every 28 days (Day 1) Laboratory Biomarker Analysis: Correlative studies

Nivolumab: Given IV Pharmacological Study: Correlative studies Veliparib: Given PO

ORR (Overall Response Rate)

Stable Disease for or ≥12 weeks

Velaparib (oral medication) twice daily and nivolumab IV over 30 minutes on days 1 and 15 of courses 1-4 and IV over 60 minutes on day 1 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Velaparib dose in Phase 1: Cohort 1: 300 mg

Nivolumab dose: Cycle 1-4: 240 mg IV every 14 days (Days 1 \& 15) + Cycle 5+: 480mg IV every 28 days (Day 1) Laboratory

Biomarker Analysis: Correlative studies

Nivolumab: Given IV Pharmacological Study: Correlative studies

Veliparib: Given PO

Velaparib (oral medication) twice daily and nivolumab IV over 30 minutes on days 1 and 15 of courses 1-4 and IV over 60 minutes on day 1 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

* Velaparib dose: 400 mg
* Nivolumab dose: Cycle 1-4: 240 mg IV every 14 days (Days 1 \& 15) + Cycle 5+: 480mg IV every 28 days (Day 1) Laboratory Biomarker Analysis: Correlative studies Nivolumab: Given IV Pharmacological Study: Correlative studies Veliparib: Given PO

Patients in all Phase 1 cohorts and Phase 2 receive velaparib (oral medication) twice daily and nivolumab IV over 30 minutes on days 1 and 15 of courses 1-4 and IV over 60 minutes on day 1 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

* Velaparib dose 400 mg
* Nivolumab dose: Cycle 1-4: 240 mg IV every 14 days (Days 1 \& 15) + Cycle 5+: 480mg IV every 28 days (Day 1) Laboratory Biomarker Analysis: Correlative studies Nivolumab: Given IV Pharmacological Study: Correlative studies Veliparib

Clinical Benefit Rate (CBR)

Velaparib PO Twice Daily + Nivolumab (Cohort 2 + Phase 2)

Progression Free Survival (PFS)

Overall Survival (OS)

Velaparib (oral medication) twice daily and nivolumab IV over 30 minutes on days 1 and 15 of courses 1-4 and IV over 60 minutes on day 1 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

* Velaparib dose in Phase 1: Cohort 1: 300 mg,
* Nivolumab dose: Cycle 1-4: 240 mg IV every 14 days (Days 1 \& 15) + Cycle 5+: 480mg IV every 28 days (Day 1) Laboratory Biomarker Analysis: Correlative studies Nivolumab: Given IV Pharmacological Study: Correlative studies Veliparib: Given PO

2 patients not included in these results as they came off treatment before 24 weeks - one withdrew consent and 1 came off treatment for palliative radiation.

Number of Patients Alive and Progression Free at 24 Weeks

Completed 1st Cycle

Went on to Cycle 2 and Beyond

On Follow-up for 3 Years

Paclitaxel

Carboplatin

Docetaxel

Albumin-Bound Paclitaxel

Pevonedistat

Tubulin Modulators

Antimitotic Agents

Pevonedistat 25 mg/m\^2, infusion, intravenously, once on Day 1 of Cycle 1, followed by pevonedistat 50 mg/m\^2, infusion, intravenously, once on Day 8 of Cycle 1.

Pevonedistat 50 mg/m\^2, infusion, intravenously, once on Day 1 of Cycle 1, followed by pevonedistat 25 mg/m\^2, infusion, intravenously, once on Day 8 of Cycle 1.

Pevonedistat 25 mg/m\^2 in combination with docetaxel 75 mg/m\^2 or pevonedistat 20 mg/m\^2 in combination with carboplatin plus paclitaxel 175 mg/m\^2, infusion, intravenously, once on Day 1 in each 21-day treatment cycle followed by pevonedistat 25 mg/m\^2 or 20 mg/m\^2 infusion, intravenously, once on Days 3 and 5 in each 21-day treatment cycle for up to 12 cycles or symptomatic deterioration or PD, treatment is discontinued for another reason, or until the study is stopped. The combination and dose of pevonedistat will be based on investigator discretion.

Medical Director

The purpose of this study is to characterize the effects of 25 and 50 milligram per square meter (mg/m\^2) pevonedistat on the Fridericia corrected QT interval (QTcF) of the electrocardiogram (ECG).

The drug being tested in this study is called pevonedistat. Pevonedistat in combination with standard of care will be used to treat participants who have advanced solid tumors. This study will assess the effects of pevonedistat on the QTc interval in participants with advanced solid tumors.

The study will enroll approximately 45 participants. The study will be conducted in two Parts: Part A and Part B. Part A will have a 2-way crossover design and will involve the collection of triplicate ECGs. In Part A, participants will be randomly assigned to one of the two treatment groups as follow:

* Pevonedistat 25 mg/m\^2 + Pevonedistat 50 mg/m\^2
* Pevonedistat 50 mg/m\^2 + Pevonedistat 25 mg/m\^2

Eligible participants from Part A will continue treatment in optional Part B with pevonedistat in combination with SoC, docetaxel or carboplatin plus paclitaxel. The investigator will decide which pevonedistat combination a participant will receive.

* Pevonedistat 25 mg/m\^2 + Docetaxel
* Pevonedistat 20 mg/m\^2 + Carboplatin + Paclitaxel

This multi-center trial will be conducted in the United States. The overall time to participate in this study is 9.6 months. Participants will make a final visit to the clinic 30 days after receiving their last dose of study drug for a follow-up assessment.

A Study to Evaluate the Effects of Pevonedistat on the Corrected QT (QTc) Interval in Participants With Advanced Solid Tumors

A Randomized, Crossover Phase 1 Study to Evaluate the Effects of Pevonedistat on the QTc Interval in Patients With Advanced Solid Tumors

Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

Change from time-matched baseline in QTcF was assessed following a single intravenous dose administration of pevonedistat at 25 and 50 mg/m\^2 and was analysed by dose. Some participants were treated with pevonedistat 25 mg/m\^2 or 50 mg/m\^2 on Day 1 while others received treatment on Day 8. Data is reported at pre-dose and at multiple timepoints (1, 2, 3, 4, 6, 9, 11 and 24 hours) postdose up to Day 8 in Part A. Analysis of variance (ANOVA) was used for the analysis.

Change from time-matched baseline in QTcI was assessed following a single intravenous dose administration of pevonedistat at 25 and 50 mg/m\^2 and was analysed by dose. Some participants were treated with pevonedistat 25 mg/m\^2 or 50 mg/m\^2 on Day 1 while others received treatment on Day 8. ANOVA was used for the analysis.

Change from time-matched baseline in QRS was assessed following a single intravenous dose administration of pevonedistat at 25 and 50 mg/m\^2 and was analysed by dose. Some participants were treated with pevonedistat 25 mg/m\^2 or 50 mg/m\^2 on Day 1 while others received treatment on Day 8. ANOVA was used for the analysis.

Change from time-matched baseline in PR was assessed following a single intravenous dose administration of pevonedistat at 25 and 50 mg/m\^2 and was analysed by dose. Some participants were treated with pevonedistat 25 mg/m\^2 or 50 mg/m\^2 on Day 1 while others received treatment on Day 8. ANOVA was used for the analysis.

Change from time-matched baseline in HR was assessed following a single intravenous dose administration of pevonedistat at 25 and 50 mg/m\^2 and was analysed by dose. Some participants were treated with pevonedistat 25 mg/m\^2 or 50 mg/m\^2 on Day 1 while others received treatment on Day 8. ANOVA was used for the analysis.

Percentage of participants who achieve an overall response per investigator's assessment at end of treatment,according to Response Evaluation Criteria in Solid Tumor(RECIST),version 1.1 guideline. Complete response(CR):Disappearance of all target lesions.Any pathological lymph nodes(whether target and non target)must have reduction in short axis to \<10 millimeter(mm).Partial Response(PR):atleast 30% decrease in sum of diameter of target lesions,taking as reference baseline sum of diameter.Stable Disease(SD):Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression(PD),taking as reference smallest sum of diameter; PD:atleast 20% increase in sum of diameter of target lesions,taking as reference,smallest sum on study(this includes baseline sum if that is smallest on study).In addition to relative increase of 20%,sum must also demonstrate an absolute increase of atleast 5 mm.Appearance of 1 or more new lesions is also considered progression.

Millennium Pharmaceuticals, Inc.

Safety Population for Part A included all participants who received at least 1 dose of pevonedistat during Part A. Safety population for Part B included all participants who continued to Part B and received at least 1 dose of study drugs during Part B. For Part A, MedDRA Version 22.0 was used and for Part B MedDRA version 24.0 was used.

Pevonedistat 25 mg/m\^2, infusion, intravenously (IV), once on Day 1, followed by pevonedistat 50 mg/m\^2, infusion, IV, once on Day 8 in Part A.

Part A: Pevonedistat 25 mg/m^2 + Pevonedistat 50 mg/m^2

Pevonedistat 50 mg/m\^2, infusion, IV, once on Day 1, followed by pevonedistat 25 mg/m\^2, infusion, IV, once on Day 8 in Part A.

Part A: Pevonedistat 50 mg/m^2 + Pevonedistat 25 mg/m^2

Pevonedistat 25 mg/m\^2 in combination with docetaxel 75 mg/m\^2, infusion, IV, once on Day 1 followed by pevonedistat 25 mg/m\^2 IV, once on Days 3 and 5 in each 21-day treatment cycle for up to Cycle 45 or symptomatic deterioration or progressive disease (PD), or until treatment is discontinued for another reason. Pevonedistat was administered after the docetaxel chemotherapy. Participants who completed Part A and provided consent for Part B continued treatment in Part B.

Part B: Pevonedistat 25 mg/m^2 + Docetaxel

Pevonedistat 20 mg/m\^2 in combination with carboplatin area under the plasma concentration (AUC) at the dose of 5 mg/min/mL, infusion, IV and paclitaxel 175 mg/m\^2, infusion, IV, once on Day 1 in each 21-day treatment cycle followed by pevonedistat 20 mg/m\^2 IV, once on Days 3 and 5 in each 21-day treatment cycle for up to 20 cycles or symptomatic deterioration or PD, or until treatment is discontinued for another reason. Pevonedistat was administered after the paclitaxel and carboplatin chemotherapy. Participants who completed Part A and provided consent for Part B continued treatment in Part B.

Part B: Pevonedistat 20 mg/m^2 + Carboplatin + Paclitaxel

Age, Continuous

Randomized Population included all participants who had a randomization date and had been randomized to a treatment sequence.

Study Director

Predose

1 Hour Postdose

2 Hours Postdose

3 Hours Postdose

4 Hours Postdose

6 Hours Postdose

9 Hours Postdose

11 Hours Postdose

24 Hours Postdose

Pevonedistat 25 mg/m\^2, infusion, IV, once on Day 1 or Day 8.

Pevonedistat 25 mg/m^2

Pevonedistat 50 mg/m\^2, infusion, IV, once on Day 1 or Day 8.

Pevonedistat 50 mg/m^2

QT Population included all participants who received the protocol-specified pevonedistat dosing and had sufficient electrocardiogram (ECG) assessments in the Baseline period (Day -1) and at least one period of assessment of effect of pevonedistat (Day 1 or Day 8) to permit reliable analysis. Overall number analyzed are the number of participants with evaluable data for analyses by dose. Number analyzed is the number of participants with data available for analysis at the given time point.

Part A: Change From Time-matched Baseline in Fridericia-corrected QT Interval (QTcF) After Pevonedistat Administration

QT Population included all participants who received the protocol-specified pevonedistat dosing and had sufficient ECG assessments in the Baseline period (Day -1) and at least one period of assessment of effect of pevonedistat (Day 1 or Day 8) to permit reliable analysis. Overall number analyzed are the number of participants with evaluable data for analyses by dose. Number analyzed is the number of participants with data available for analysis at the given time point.

Part A: Change From Time-matched Baseline in Individual Corrected QT Interval (QTcI) After Pevonedistat Administration

Part A: Change From Time-matched Baseline in QRS After Pevonedistat Administration

Part A: Change From Time-matched Baseline in PR After Pevonedistat Administration

Part A: Change From Time-matched Baseline in Heart Rate (HR) After Pevonedistat Administration

Pharmacokinetic (PK) Population included all participants who received the protocol-specified pevonedistat dosing during Part A and had sufficient PK assessments to permit reliable estimation of PK parameters. Overall number analyzed are the number of participants with evaluable data for analyses by dose.

Part A: Cmax: Maximum Observed Plasma Concentration for Pevonedistat

PK Population included all participants who received the protocol-specified pevonedistat dosing during Part A and had sufficient PK assessments to permit reliable estimation of PK parameters. Overall number analyzed are the number of participants with evaluable data for analyses by dose.

Part A: AUC(0-24): Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Postdose for Pevonedistat

PK Population included all participants who received the protocol-specified pevonedistat dosing during Part A and had sufficient PK assessments to permit reliable estimation of PK parameters. Overall number analyzed are the number of participants with evaluable data for analyses.

Part A: Terminal Phase Elimination Half-life (t1/2) for Pevonedistat

Disease-response population included participants who received at least 1 dose of study drug in Part B, had measurable disease as entry criteria for Part B, and had at least 1 postbaseline disease assessment.

Part B: Overall Response Rate (ORR)

Pevonedistat 20 mg/m\^2 in combination with carboplatin area under the plasma concentration (AUC) at the dose of 5 milligram per minute per milliliter (mg/min/mL), infusion, IV and paclitaxel 175 mg/m\^2, infusion, IV, once on Day 1 in each 21-day treatment cycle followed by pevonedistat 20 mg/m\^2 IV, once on Days 3 and 5 in each 21-day treatment cycle for up to 20 cycles or symptomatic deterioration or PD, or until treatment is discontinued for another reason. Pevonedistat was administered after the paclitaxel and carboplatin chemotherapy. Participants who completed Part A and provided consent for Part B continued treatment in Part B.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Nivolumab and Veliparib in Treating Patients With Recurrent or Refractory Stage IV Solid Tumors That Cannot Be Removed by Surgery or Lymphoma With or Without Alterations in DNA Repair Genes	NCT03061188	Advanced Solid ... Aggressive Non-... Recurrent Solid... Refractory Mant... T-Cell Non-Hodg... Unresectable So...	Laboratory Biom... Nivolumab Pharmacological... Veliparib	18 Years -	Northwestern University
A Study to Evaluate the Effects of Pevonedistat on the Corrected QT (QTc) Interval in Participants With Advanced Solid Tumors	NCT03330106	Advanced Solid ...	Pevonedistat Docetaxel Carboplatin Paclitaxel	18 Years -	Takeda
A Study to Evaluate the Effects of Pevonedistat on the Corrected QT (QTc) Interval in Participants With Advanced Solid Tumors	NCT03330106	Advanced Solid ...	Pevonedistat Docetaxel Carboplatin Paclitaxel	18 Years -	Takeda

Spots Global Cancer Trial Database for advanced solid neoplasm