Study of MLN2480 in Participants With Relapsed or Refractory Solid Tumors Followed by a Dose Expansion in Participants With Metastatic Melanoma

Study Overview
=================
Brief Summary
-----------------
This is a phase 1, multicenter, nonrandomized, open-label, dose escalation study. The study will be conducted in 2 stages, Dose Escalation and Dose Expansion. The Dose Escalation phase will include participants with solid tumors (including melanoma) who have failed or are not candidates for standard therapies or for whom no approved therapy is available. The Dose Expansion phase will include participants with metastatic melanoma.

Official Title
-----------------
An Open-Label, Phase 1, Dose Escalation Study of MLN2480 in Patients With Relapsed or Refractory Solid Tumors Followed by a Dose Expansion Phase in Patients With Metastatic Melanoma

Conditions
-----------------
Melanoma, Metastatic Melanoma, Solid Tumor, Neoplasm

Intervention / Treatment
-----------------
* Drug: MLN2480


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Informed consent. Male or female participants 18 years or older. Dose Escalation phase: Participants with solid tumors (including melanoma) who have failed or are not candidates for standard therapies of for whom no approved therapy is available. Dose Expansion phase: Metastatic melanoma (locally advanced or metastatic melanoma). Dose Expansion phase: At least 1 measurable lesion which has not been treated previously with radiotherapy. A newly arising lesion in a previously irradiated field is acceptable. For participants undergoing biopsy procedures: Prothrombin time (PT) and activated partial thromboplastin time (aPTT) must be within the normal range. Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to (<=) 1. Adequate tissue sample from either archival formalin-fixed paraffin-embedded (FFPE) tumor tissue or new biopsy of tumor. Previous chemotherapy, immunotherapy, and hormone therapy must be completed at least 4 weeks prior to the administration of MLN2480 and radiation must be completed at least 3 weeks prior to the administration of MLN2480; all associated toxicity must be resolved to <=Grade 1. Expected survival time of at least 3 months in the opinion of the investigator. Participants who do not have hypo- or hyperthyroidism. Ability to swallow and retain oral medication. Female participants who are postmenopausal for at least 1 year, surgically sterile, or agree to practice 2 effective methods of contraception through 3 months after the last dose of study drug or agree to practice true abstinence. Male participants who, even if surgically sterilized, agree to practice effective barrier contraception through 3 months after the last dose of alisertib or agree to practice true abstinence. Exclusion Criteria History of any major disease that might interfere with safe protocol participation. Dose Expansion phase: Previous treatment with RAF or MEK inhibitors. Laboratory values as specified in study protocol. Current enrollment in any other investigational treatment study. Evidence of current uncontrolled cardiovascular conditions within the past 6 months. Prior investigational agents for malignant or non-malignant disease within 4 weeks prior to Day 1. Active hepatitis or human immunodeficiency virus (HIV) infection. Active bacterial or viral infection. Female participants who are pregnant or currently breastfeeding. Major surgery within 28 days of Day 1. Refractory nausea and vomiting, malabsorption, or significant bowel or stomach resection. Inability to comply with study requirements. Other unspecified reasons that, in the opinion of the investigator or Millennium, make the participant unsuitable for enrollment.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MLN2480<br> | Drug: MLN2480<br>* Dose Escalation Phase: participants will receive MLN2480 orally in escalating doses every other day or once weekly for three weeks of a 28-day cycle. Participants may continue treatment for additional cycles (up to 12 months) until disease progression, unacceptable toxicity, or the participant discontinues for any other reason. If it is determined that a participant would derive benefit from continued therapy beyond 12 months treatment may continue. Dose Expansion Phase: Participants will take MLN2480 at the maximum tolerated dose orally every other day or once weekly for three weeks of a 28-day cycle until disease progression, unacceptable toxicity, or the participant discontinues for any other reason. The maximum duration of treatment is 1 year unless determined that a participant would derive benefit from continued therapy beyond 12 months.<br>* Other names: TAK-580;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Deaths |  | Baseline up to 30 days after last dose, or start of subsequent therapy, whichever occurred first (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle=22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle=28 days] in Expansion Phase) | 
| Dose Escalation Phase: Number of Participants With Dose-limiting Adverse Events (AEs) | Dose limiting AEs were evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. Dose limiting AEs were defined as any of the following events: Grade 4 neutropenia for more than 7 days under maximum supportive therapy; febrile neutropenia; platelet counts decreased of Grade 3 requiring platelet transfusion or blood platelet decreased of Grade 4; if Course 2 was not initiated within 14 days due to AE related to the protocol treatment; Grade 3 or higher non-hematologic toxicity that was considered clinically significant, except the following cases, Grade 3 gastrointestinal symptoms that could be controlled with supportive therapy (example, appropriate use of antiemetics, antidiarrheals), and Grade 3 or higher electrolyte abnormalities that were not deemed clinically significant. | Cycle 1 (Cycle length= 22 days [Q2D] and 28 days [QW]) | 
| Number of Participants With TEAEs Related to Physical Examination Findings |  | Baseline up to 30 days after last dose, or start of subsequent therapy, whichever occurred first (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle=22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle=28 days] in Expansion Phase) | 
| Clinically Significant Change From Baseline in Body Weight at End of Study Visit (EOSV) |  | Baseline up to EOSV (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle length =22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle length =28 days] in Expansion Phase) | 
| Number of Participants With Abnormal Clinically Significant Electrocardiogram (ECG) Findings |  | Baseline up to 30 days after last dose, or start of subsequent therapy, whichever occurred first (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle=22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle=28 days] in Expansion Phase) | 
| Eastern Cooperative Oncology Group (ECOG) Performance Score | ECOG performance score was measured on 6 point scale to assess participant's performance status, where: 0 (fully active, able to carry on all pre-disease activities without restriction); 1 (restricted in physically strenuous activity, but ambulatory and able to carry out light or sedentary work); 2 (ambulatory greater than(>) 50 percent (%) of waking hours), capable of all self-care, unable to carry out any work activities); 3 (capable of only limited self-care, confined to bed or chair >50% of waking hours); 4(completely disabled, cannot carry on any self-care, totally confined to bed or chair); 5 (dead). A higher score indicated greater functional impairment. | at EOSV (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle length =22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle length =28 days] in Expansion Phase) | 
| Number of Participants With TEAEs Categorized Into Investigations Related to Laboratory Test of Chemistry, Hematology or Urinalysis |  | Baseline up to 30 days after last dose, or start of subsequent therapy, whichever occurred first (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle=22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle=28 days] in Expansion Phase) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR was defined as the percentage of participants with complete response (CR) or partial response (PR). The ORR assessment was based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR: was disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to less than (<) 10 millimeter (mm). PR: was at least a 30% decrease in sum of diameter (SOD) of target lesions, taking as reference the baseline SOD. | Baseline up to EOSV (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle length =22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle length =28 days] in Expansion Phase) | 
| Progression-free Survival (PFS) | PFS was the time from first dose date of study drug to date of the first documentation of confirmed progressive disease (PD) or death, whichever occurred first. The PFS assessment was based on RECIST 1.1. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions. PFS was calculated using Kaplan-Meier estimate and presented with 2-sided 95% confidence interval. Participants with no response assessment were censored at the date of first dose. | Baseline up to the date of first document PD, or death due to any cause, whichever occurred first (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle =22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle =28 days] in Expansion Phase) | 
| Duration of Response (DOR) | DOR was assessed from the first documented response (CR or PR) to the date of first documented PD and was censored at the date of the last assessment for responders who died without documented PD and for responders who were still alive and had not progressed. DOR assessment was based on RECIST v1.1. CR: was disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to <10 mm. PR: at least 30% decrease in SOD of target lesions, taking as reference the baseline SOD persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. DOR was calculated using Kaplan-Meier estimate. | From the first documented response (CR or PR) up to the date of first documented PD (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle =22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle =28 days] in Expansion Phase) | 
| Dose Escalation Phase and Dose Expansion Pharmacokinetic Cohort, Cmax: Maximum Observed Plasma Concentration for TAK-580 |  | Escalation (Esc.) and Expansion (Exp.) Q2D: C1D1 and 21 pre-dose and at multiple time points (up to 48 hours [h]) post-dose (C=22 days [Esc. Q2D] and 28 days [Exp. Q2D]); Esc. QW: C1D1 and 22 at multiple time-points (up to168 h) post-dose (C=28 days) | 
| Dose Escalation Phase and Dose Expansion Pharmacokinetic Cohort, Ctrough: Trough Concentration for TAK-580 |  | Escalation and Expansion Q2D Cohorts: C1D21 pre-dose (C=22 days [Escalation Q2D] and 28 days [Expansion Q2D]); Escalation QW Cohorts: C1D22 pre-dose (C= 28 days) | 
| Dose Escalation Phase and Dose Expansion Pharmacokinetic Cohort, Tmax: Time to Reach the Cmax for TAK-580 |  | Escalation (Esc.) and Expansion (Exp.) Q2D: C1D1 and 21 pre-dose and at multiple time points (up to 48 h) post-dose (C=22 days [Esc. Q2D] and 28 days [Exp. Q2D]); Esc. QW: C1D1 and 22 at multiple time-points (up to168 h) post-dose (C=28 days) | 
| Dose Escalation Phase and Dose Expansion Pharmacokinetic Cohort, t1/2z: Terminal Phase Disposition Half-life for TAK-580 |  | Escalation (Esc.) and Expansion (Exp.) Q2D: C1D21 pre-dose and at multiple time points (up to 48 h) post-dose (C=22 days [Esc. Q2D] and 28 days [Exp. Q2D]); Esc. QW: C1D22 at multiple time-points (up to168 h) post-dose (C=28 days) | 
| Dose Escalation Phase and Dose Expansion Pharmacokinetic Cohort, CLr: Renal Clearance for TAK-580 |  | Q2D Cohorts: Cycle1 Days 1 and 21 up to 24 hours post-dose (Cycle1 length= 22 days); QW Cohorts: Cycle2 Days 1 and 22 up to 7 hours post-dose (Cycle 2 length= 28 days) | 
| Q2D Dose Escalation Phase and Q2D Dose Expansion Pharmacokinetic Cohort, AUC(0-48): Area Under the Plasma Concentration-time Curve From Time 0 to 48 Hours Postdose for TAK-580 |  | Cycle 1 Days 1 and 21 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length= 22 days) | 
| QW Dose Escalation Phase, AUC(0-168): Area Under the Plasma Concentration-time Curve From Time 0 to 168 Hours Postdose for TAK-580 |  | Cycle 1 Days 1 and 22 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length= 28 days) | 
| Dose Expansion Phase, Melanoma Cohorts: Percent Change From Baseline in RAF Inhibition Biomarkers at Specified Time Points | The extent of phosphorylated extracellular signal-regulated kinase (pERK) staining was assessed in the melanoma expansion cohorts. The level of staining was assessed by a pathologist (semi-H scores) and by quantified image analysis (quant H-scores). The H-score scale used to interpret data from the pathologist rating was as follows: 0 to 99 =low staining; 100 to 199= medium staining; 200 to 300 =high staining. The H-score scale used to interpret data from the quantified image analysis was as followed: 0 to 100 =low staining; 100 to 150= medium staining; 150 to 235= high staining. | Baseline, Cycle 1 Day 21 (Q2D), and Cycle 1 Day 22 (QW) (Cycle length= 22 days [Q2D] and 28 days [QW]) | 
| Dose Expansion Phase, Melanoma Cohorts: Percent Change From Baseline in Apoptotic Biomarkers at Specified Time Points | The extent of cleaved poly ADP-ribose polymerase (cPARP) and BIM-1 was assessed in the melanoma expansion cohorts. The level of staining was assessed by quantified image analysis (quant H-scores) and by quantified image analysis (quant H-scores). The H-score scale used to interpret data from the pathologist rating was as follows: 0 to 99= low staining; 100 to 199 =medium staining; 200 to 300 =high staining. The H-score scale used to interpret data from the quantified image analysis was as followed in cPARP: 0 to 70= low staining; 70 to 175 =medium staining; 175 to 240 =high staining; BIM-1: 0 to 128= low staining; 128 to 155 =medium staining; 155 to 229 =high staining. | Baseline, Cycle 1 Day 21 (Q2D), and Cycle 1 Day 22 (QW) (Cycle length= 22 days [Q2D] and 28 days [QW]) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Drug Therapy