Study of MLN8237 in Participants With Advanced Hematological Malignancies

Study Overview
=================
Brief Summary
-----------------
This is an open-label, multicenter, phase 1 study of MLN8237 in participants with advanced hematological malignancies for whom there are limited standard treatment options.

Detailed Description
-----------------
The drug being tested in this study is called alisertib. Alisertib is being tested to treat people who have advanced hematological malignancies. This study determined the dose-limiting toxicity, maximum tolerated dose, safety and pharmacokinetics (how the drug moves through the body) for alisertib when given once or twice a day for 7 to 21 days. This open label study enrolled 58 patients. Participants were enrolled in one of 3 treatment groups: Part 1: Powder-in-Capsule (PIC) Dose Escalation (alisertib 25 mg PIC, orally twice daily [BID] on Day 1 [loading dose] and then alisertib 25 or 35 mg PIC once daily [QD] for 21 days (D), or alisertib 35, 45, 65 or 90 mg PIC, orally, QD for 14D) in 28-day cycles Part 1: Enteric-coated Tablet (ECT) Dose Escalation (alisertib 40 mg, ECT, orally, QD for 14D or alisertib 30, 40 or 50 mg, orally, BID for 7D) in 28-day cycles Part 2: Participants with Peripheral T-cell Lymphoma (PTCL) (alisertib 50 mg ECT, orally, BID for 7D) in 21-day cycles All participants received treatment for 12 months or until their disease progressed or they experienced unacceptable alisertib-related toxicity. This multi-center trial was conducted in the United States. The overall time to participate in this study was 422 days. Participants made multiple visits to the clinic, including a final visit 30 days after receiving their last dose of alisertib for a follow-up assessment.

Official Title
-----------------
An Open-label, Phase 1 Study of MLN8237, a Novel Aurora A Kinase Inhibitor, in Patients With Advanced Hematological Malignancies

Conditions
-----------------
B-cell Follicular Lymphoma, B-cell Marginal Zone Lymphoma, Diffuse Large B-cell Lymphoma, B-cell Mantle Cell Lymphoma, B-cell Small Lymphocytic Lymphoma, B-Cell Chronic Lymphocytic Leukemia, Multiple Myeloma, Waldenstrom's Macroglobulinemia, Noncutaneous Peripheral T-cell Lymphoma Not Otherwise Specified, Angioimmunoblastic T-cell Lymphoma, Anaplastic Large Cell Lymphoma, Enteropathy Associated T-cell Lymphoma, NK Lymphoma

Intervention / Treatment
-----------------
* Drug: Alisertib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Relapsed or refractory disease and a histologically or cytologically confirmed hematological malignancy of the following type for which standard curative treatment does not exist or is no longer effective: B-cell Follicular lymphoma B-cell Marginal zone lymphoma Diffuse large B-cell lymphoma B-cell Mantle cell lymphoma B-cell Small lymphocytic lymphoma (SLL) B-Cell Chronic lymphocytic leukemia (B-CLL) Multiple myeloma Waldenstrom's macroglobulinemia Noncutaneous peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) Angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell lymphoma, enteropathy associated T-cell lymphoma (EATCL), NK lymphoma (NKL) Participants with diffuse large B-cell lymphoma must have failed, be ineligible for, or have refused an autologous stem cell transplant. There is no restriction regarding the maximum number of prior regimens. Aged 18 years or older Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 Radiographically or clinically evaluable disease for Part 1 of this study and measurable disease for Part 2 of this study Suitable venous access for the conduct of blood sampling for MLN8237 pharmacokinetics (PK) Recovered from the reversible effects of prior antineoplastic treatment (with the exception of alopecia and Grade 1 neuropathy) Exclusion Criteria: Pregnant or lactating Treatment with clinically significant enzyme inducers within 14 days prior to the first dose of MLN8237 as specified in the protocol Prior allogeneic bone marrow (or other organ) transplantation Newly diagnosed or uncontrolled cancer-related central nervous system (CNS) disease Systemic antineoplastic treatment within 21 days preceding the first dose of study treatment. Exceptions requiring a 42-day recovery period from last treatment include: Nitrosoureas, mitomycin C or Rituximab, alemtuzumab (Campath®), or other unconjugated therapeutic antibody (21 days if clear evidence of progressive disease) Treatment with radioimmunoconjugates or toxin immunoconjugates such as ibritumomab tiuxetan (Zevalin™), or tositumomab (Bexxar®) within 56 days preceding the first dose of study treatment Antineoplastic treatment with glucocorticoids within 21 days preceding the first dose of study treatment Radiotherapy involving <25% of the hematopoietically active bone marrow within 21 days preceding first dose of study treatment Radiotherapy involving ≥25% of the hematopoietically active bone marrow within 42 days preceding first dose of study treatment Inability to swallow capsules or known gastrointestinal (GI) disease or GI procedures that could interfere with the oral absorption or tolerance of MLN8237. Examples include, but are not limited to, partial gastrectomy, history of small intestine surgery, and celiac disease. History of uncontrolled sleep apnea syndrome and other conditions that could result in excessive daytime sleepiness such as severe chronic obstructive pulmonary disease Known or suspected human immunodeficiency virus (HIV) positive or hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection. Testing is not required in the absence of clinical findings or suspicion. Participants who fail to meet laboratory values as specified in the protocol during the screening period

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: PIC Dose Escalation<br>Alisertib 25 or 35 mg, Powder-in-Capsule (PIC) formulation, orally, once daily (QD) for 21 days followed by a 7-day recovery period in 28-day cycles or alisertib 35, 45, 65 or 90 mg PIC, orally, (QD for 14 days followed by a 14-day recovery period in 28-day cycles, until disease progression or unacceptable alisertib-related toxicity (up to 14 cycles). All participants received an initial starting dosage of alisertib PIC 25 mg, orally, twice daily (BID) on Day 1 (loading dose), followed by their respective dosage assignment. | Drug: Alisertib<br>* Alisertib (MLN8237) PIC or ECT<br>* Other names: MLN8237;|
| Experimental: Part 1: ECT Dose Escalation<br>Alisertib 40 mg, Enteric-coated Tablet (ECT) formulation, orally, QD for 14 days followed by a 14-day recovery period in 28-day cycles, or alisertib 30, 40 or 50 mg ECT, orally BID for 7 days followed by a 14-day recovery period in 21-day cycles, until disease progression or unacceptable alisertib-related toxicity (up to 15 cycles). | Drug: Alisertib<br>* Alisertib (MLN8237) PIC or ECT<br>* Other names: MLN8237;|
| Experimental: Part 2: PTCL<br>Participants with peripheral T-cell lymphoma (PTCL) received alisertib 50 mg ECT, orally, BID for 7 days followed by a 14-day recovery period in 21-day cycles, until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles). | Drug: Alisertib<br>* Alisertib (MLN8237) PIC or ECT<br>* Other names: MLN8237;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose-Limiting Toxicity (DLT) | DLT was evaluated according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0 and was defined as any of the following events related to therapy with alisertib:1. Grade 4 neutropenia lasting ≥7 consecutive days, 2. Grade 4 neutropenia with fever and/or infection 3. Platelet count <25,000/mm^3 4. Grade 3 or greater nausea and/or emesis despite use of optimal antiemetic prophylaxis 5. Grade 3 or greater diarrhea despite maximal supportive therapy with loperamide 6. Any other Grade 3 or greater nonhematologic toxicity, with the following exceptions: Grade 3 arthralgia/myalgias, Any grade of alopecia, Brief (<1 week) Grade 3 fatigue 7. Treatment delay of >21 days due to failure of adequate hematologic or non-hematologic recovery from previous cycle of treatment 8. Other alisertib related non-hematologic toxicities ≥Grade 2 that, in the opinion of the investigator required a dose reduction or discontinuation of therapy with alisertib. | From first dose of study drug to 30 days after the last dose (up to 422 days) | 
| Maximum Tolerated Dose (MTD) of Alisertib | MTD was defined as the highest dose at which DLT occurred in 0/3 or 1/6 participants. | From first dose of study drug to 30 days after the last dose (up to 422 days) | 
| Cmax: Maximum Observed Concentration for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 1 |  | Cycle 1 Day 1 predose and at multiple timepoints (up to 24 hours) postdose | 
| Cmax: Maximum Observed Concentration for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21 |  | Cycle 1 Day 21 predose and at multiple timepoints (up to 6 hours) postdose | 
| Tmax: Time of First Occurrence of Cmax for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 1 |  | Cycle 1 Day 1 predose and at multiple timepoints (up to 24 hours) postdose | 
| Tmax: Time of First Occurrence of Cmax for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21 |  | Cycle 1 Day 21 predose and at multiple timepoints (up to 6 hours) postdose | 
| AUCt: Area Under the Concentration Time Curve From Time 0 to Time t for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21 |  | Cycle 1 Day 21 predose and at multiple time points (up to 6 hours) postdose | 
| Terminal Half-Life (t1/2) for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21 |  | Cycle 1 Day 21 predose and at multiple time points (up to 6 hours) postdose | 
| Accumulation Ratio (Rac) for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21 |  | Cycle 1 Day 21 predose and at multiple time points (up to 6 hours) postdose | 
| Peak/Trough Ratio for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21 |  | Cycle 1 Day 21 predose and at multiple timepoints (up to 6 hours) postdose | 
| CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21 |  | Cycle 1 Day 21 predose and at multiple timepoints (up to 6 hours) postdose | 
| Cmax: Maximum Observed Concentration for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 1 |  | Cycle 1 Day 1 predose and at multiple timepoints (up to 24 hours) postdose | 
| Cmax: Maximum Observed Concentration for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 14 |  | Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose | 
| Tmax: Time of First Occurrence of Cmax for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 1 |  | Cycle 1 Day 1 predose and at multiple timepoints (up to 24 hours) postdose | 
| Tmax: Time of First Occurrence of Cmax for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 14 |  | Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose | 
| AUCt: Area Under the Concentration Time Curve From Time 0 to Time t for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 14 |  | Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose | 
| Accumulation Ratio (Rac) for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 14 |  | Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose | 
| Peak/Trough Ratio for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 14 |  | Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose | 
| CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 14 |  | Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose | 
| Cmax: Maximum Observed Concentration for Alisertib as Enteric Coated Tablet (ECT) With Once Daily for 14 Days (QD14D) Dosing at Day 1 |  | Cycle 1 Day 1 predose and at multiple timepoints (up to 24 hours) postdose | 
| Cmax: Maximum Observed Concentration for Alisertib as Enteric Coated Tablet (ECT) With Once Daily for 14 Days (QD14D) Dosing at Day 14 |  | Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose | 
| Tmax: Time of First Occurrence of Cmax for Alisertib as Enteric Coated Tablet (ECT) With Once Daily for 14 Days (QD14D) Dosing at Day 1 |  | Cycle 1 Day 1 predose and at multiple timepoints (up to 24 hours) postdose | 
| Tmax: Time of First Occurrence of Cmax for Alisertib as Enteric Coated Tablet (ECT) With Once Daily for 14 Days (QD14D) Dosing at Day 14 |  | Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose | 
| AUCt: Area Under the Concentration Time Curve From Time 0 to Time t for Alisertib as Enteric Coated Tablet (ECT) With Once Daily for 14 Days (QD14D) Dosing at Day 14 |  | Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose | 
| Terminal Half Life for Alisertib as Enteric Coated Tablet (ECT) With Once Daily for 14 Days (QD14D) Dosing at Day 14 |  | Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose | 
| Peak/Trough Ratio for Alisertib as Enteric Coated Tablet (ECT) With Once Daily for 14 Days (QD14D) Dosing at Day 14 |  | Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose | 
| CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Enteric Coated Tablet (ECT) With Once Daily for 14 Days (QD14D) Dosing at Day 14 |  | Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose | 
| Cmax: Maximum Observed Concentration for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 1 |  | Cycle 1 Day 1 predose and at multiple timepoints (up to 12 hours) postdose | 
| Cmax: Maximum Observed Concentration for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7 |  | Cycle 1 Day 7 predose and at multiple timepoints (up to 12 hours) postdose | 
| Tmax: Time of First Occurrence of Cmax for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 1 |  | Cycle 1 Day 1 predose and at multiple timepoints (up to 12 hours) postdose | 
| Tmax: Time of First Occurrence of Cmax for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7 |  | Cycle 1 Day 7 predose and at multiple timepoints (up to 12 hours) postdose | 
| AUCt: Area Under the Concentration Time Curve From Time 0 to Time t for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 1 |  | Cycle 1 Days 1 predose and at multiple timepoints (up to 12 hours) postdose | 
| AUCt: Area Under the Concentration Time Curve From Time 0 to Time t for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7 |  | Cycle 1 Day 7 predose and at multiple timepoints (up to 12 hours) postdose | 
| Terminal Half-Life (t1/2) for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7 |  | Cycle 1 Day 7 predose and at multiple timepoints (up to 12 hours) postdose | 
| Accumulation Ratio (Rac) for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7 |  | Cycle 1 Day 7 predose and at multiple timepoints (up to 12 hours) postdose | 
| Peak/Trough Ratio for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7 |  | Cycle 1 Day 7 predose and at multiple timepoints (up to 12 hours) postdose | 
| CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7 |  | Cycle 1 Day 7 predose and at multiple timepoints (up to 12 hours) postdose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response Rate Based on Investigator's Assessment | Best overall response rate is defined as the percentage of participants with complete response (CR) or partial response (PR) as assessed by the Investigator using International Working Group (IWG) Criteria. CR is defined as the disappearance of all evidence of disease and the definition for PR includes at least a 50% decrease in sum of the product of the diameters and no new lesions. | Baseline and every 2 cycles up to Month 12 until disease progression, 30 days after end of treatment (up to 422 days) | 
| Duration of Response (DOR) | DOR is defined as the time from the date of first documentation of a response (either CR or PR) to the date of first documentation of progressive disease (PD) according to International Working Group (IWG) criteria. CR is defined as the disappearance of all evidence of disease and the definition for PR includes at least a 50% decrease in sum of the product of the diameters and no new lesions. PD is defined as any new lesion or increase by >50% of previously involved sites from nadir. | Baseline and every 2 cycles up to Month 12 until disease progression, 30 days after end of treatment (up to 422 days) | 
| Number of Participants With Polymorphisms in Gene Encoding Enzyme UGT1A1 | One peripheral blood sample (approximately 4 mL) was to be obtained on Day 1 of Cycle 1 prior to the first dose of alisertib to genotype participants for polymorphisms in UGT1A1 because UGT1A1 is one of the enzymes responsible for glucuronidation of alisertib, which is expected to contribute to the clearance of alisertib. wt=wild type. *28=polymorphism in the promoter region of a UGT1A1 allele resulting in reduced UGT1A1 expression. Not determined = blood sample was not evaluable. | Cycle 1 Day 1 predose | 
| Number of Participants With Polymorphisms in Aurora A Kinase |  | Cycle 1 Day 1 predose | 

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