Alisertib (MLN8237) or Investigator's Choice in Patients With Relapsed/Refractory Peripheral T-Cell Lymphoma

Study Overview
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Brief Summary
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This is a phase 3, randomized, 2-arm, open-label, international trial evaluating alisertib compared with single-agent treatment, as selected by the investigator from the offered options of pralatrexate or gemcitabine or romidepsin, in participants with relapsed or refractory peripheral T-cell lymphoma (PTCL). Note: romidepsin was not used as a single-agent comparator outside the United States of America (USA) as supply was not available.

Detailed Description
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The drug being tested in this study was Alisertib. Alisertib was tested to treat people who have relapsed/refractory peripheral T-cell lymphoma (PTCL). This study evaluated alisertib for the improvement in overall response rate (ORR) compared with single-agent treatment, as selected by the investigator from the offered options of pralatrexate, romidepsin (US only), or gemcitabine, in participants with relapsed or refractory PTCL. The study enrolled 271 patients. Participants were randomized (1:1) to one of 2 treatment arms: Alisertib Investigator's choice (Pralatrexate, Romidepsin, or Gemcitabine) This multi-center trial was conducted worldwide. The overall time to participate in this study was approximately 5 years. Participants made multiple visits to the clinic, and then were contacted by telephone up to 42-months after the last participant was randomized, or until death, for follow-up assessment.

Official Title
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A Phase 3, Randomized, Two-Arm, Open-Label, Multicenter, International Trial of Alisertib (MLN8237) or Investigator's Choice (Selected Single Agent) in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma

Conditions
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Relapsed Peripheral T-Cell Lymphoma, Refractory Peripheral T-Cell Lymphoma

Intervention / Treatment
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* Drug: Alisertib
* Drug: Pralatrexate
* Drug: Gemcitabine
* Drug: Romidepsin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female participants age 18 or older Participants with Peripheral T cell lymphoma (PTCL) (selected subtypes) according to World Health Organization (WHO) criteria and have relapsed or are refractory to at least 1 prior systemic, cytotoxic therapy for PTCL. Participants must have received conventional therapy as a prior therapy. Cutaneous-only disease is not permitted. Participants must have documented evidence of progressive and measurable disease. Tumor biopsy available for central hematopathologic review Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 Female participants who are post menopausal for at least 1 year, surgically sterile, or agree to practice 2 effective methods of contraception through 30 days after the last dose of study drug or agree to abstain from heterosexual intercourse. Male participants who agree to practice effective barrier contraception through 6 months after the last dose of alisertib or agree to abstain from heterosexual intercourse Suitable venous access Voluntary written consent Exclusion Criteria Known central nervous system lymphoma Systemic antineoplastic therapy, immunotherapy, investigational agent or radiation therapy within 4 weeks of first dose of study treatment or concomitant use during study Prior administration of an Aurora A kinase-targeted agent, including alisertib; or all of the 3 comparator drugs (pralatrexate, or romidepsin or gemcitabine; or known hypersensitivity) History of uncontrolled sleep apnea syndrome or other conditions that could result in excessive daytime sleepiness Cardiac condition as specified in study protocol, including left ventricular ejection fraction (LVEF) <40% Concomitant use of other medicines as specified in study protocol Participants with abnormal gastric or bowel function who require continuous treatment with H2-receptor antagonists or proton pump inhibitors Known active infection with human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C Autologous stem cell transplant less than 3 months prior to enrollment Participants who have undergone allogeneic stem cell or organ transplantation any time Inadequate blood levels, bone marrow or other organ function as specified in study protocol The participant must have recovered to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade ≤ 1 toxicity, to participant's baseline status (except alopecia), or deemed irreversible from the effects of prior cancer therapy Major surgery, serious infection, or infection requiring systemic antibiotic therapy within 14 days prior to the first dose of study treatment Female participants who are breastfeeding or pregnant Coexistent second malignancy or history of prior solid organ malignancy within previous 3 years Serious medical or psychiatric illness or laboratory abnormality that could, in the investigator's opinion, potentially interfere with the completion of treatment according to the protocol

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Alisertib<br>Alisertib 50 mg, enteric-coated tablet formulation, orally, twice daily for 7 consecutive days (Cycle Days 1-7) in a 21-day cycle (Up to 148 Weeks). | Drug: Alisertib<br>* Alisertib enteric coated tablets<br>|
| Active Comparator: Pralatrexate, or Romidepsin, or Gemcitabine<br>Pralatrexate 30 mg/m^2, intravenous (IV) push over 3 to 5 minutes, once weekly, for 6 weeks in 7-week cycles with concurrent vitamin B12 and folic acid supplementation. Cycles were repeated every 7-weeks provided the participant continued to benefit from and tolerate the therapy (Up to 115 Weeks), or Gemcitabine 1,000 mg/m^2 over 30 minutes, intravenously, on Days 1, 8, and 15 of a 28-day cycle until the absence of disease progression or unacceptable toxicity (Up to 32 Weeks), or Romidepsin 14 mg/m^2, intravenously over a 4-hour period, on Days 1, 8, and 15 of a 28-cycle. Cycles were repeated every 28 days provided the patient continued to benefit from and tolerate the therapy (Up to 30 Weeks). | Drug: Pralatrexate<br>* Pralatrexate IV infusion<br>Drug: Gemcitabine<br>* Gemcitabine IV infusion<br>Drug: Romidepsin<br>* Romidepsin IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) Based on Independent Review Committee (IRC) Assessment | ORR was defined as the percentage of participants who achieve Complete Response (CR) or Partial Response (PR) as assessed by the IRC using International Working Group (IWG) criteria. CR=Disappearance of all evidence of disease and PR=Regression of measurable disease and no new sites. | Every 8 weeks from date of first dose treatment; every 12 weeks after 40 week assessment; at end of treatment visit until progressive disease. Duration is approximately 3 years | 
| Progression-Free Survival (PFS) Based on IRC Assessment | PFS was defined as the time from the date of randomization to the date of first documentation of progressive disease (PD) or death due to any cause, whichever occurred first. | Every 8 weeks from date of first dose treatment; every 12 weeks after 40 week assessment; at end of treatment visit until progressive disease. Duration is approximately 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS was defined as the time from the date of randomization to the date of death. Participants without documentation of death were censored at the date last known to be alive. | Participants were followed for survival for 2 years from date of last participant off study treatment, or death, whichever occurs first. Contacts were every 4 months (Median follow-up 519 days in the alisertib arm and 586 days in the comparative arm) | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug. A SAE is any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/ birth defect or is a medically important event. | First dose to 30 days after last dose of study drug or comparator (Up to 152 Weeks) | 
| Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Clinical laboratory tests included chemistry, hematology and urinalysis test. Clinically significant treatment-emergent laboratory abnormalities were reported by the investigator as TEAEs. | First dose to 30 days after last dose of study drug or comparator (Up to 152 Weeks) | 
| Number of Participants With Clinically Important Vital Sign Measurements Reported as AEs | Vital signs included blood pressure, heart rate and temperature. Individual clinically significant changes in vital signs were reported by the investigator as TEAEs. | First dose to 30 days after last dose of study drug or comparator (Up to 152 Weeks) | 
| Complete Response (CR) Rate | Complete Response (CR) rate is defined as the percentage of participants with CR as assessed by the IRC using IWG criteria (2007 Cheson). CR= Disappearance of all evidence of disease. | At the end of every 8 weeks from date of first dose treatment; every 12 weeks after 40 week assessment; at end of treatment visit until PD (approximately 3 years) | 
| Time to Disease Progression (TTP) | Time to Progression (TTP) was defined as the time from the date of randomization to the date of first documentation of PD/relapse. | At the end of every 8 weeks from date of first dose treatment; every 12 weeks after 40 week assessment; at end of treatment visit until progressive disease. Duration is approximately 3 years | 
| Duration of Response (DOR) | DOR was defined as the time from the date of first documentation of a PR or better to the date of first documentation of progressive disease (PD)/relapse for responders as assessed by the IRC using IWG criteria. Responders without documentation of PD/relapse were censored at the date of last response assessment that was stable disease (SD) or better. | At the end of every 8 weeks from date of first dose treatment; every 12 weeks after 40 week assessment; at end of treatment visit until progressive disease. Duration is approximately 3 years | 
| Time to Response | Time to Response is defined as the time from the date of randomization to the date of first documentation of PR or better. | At the end of every 8 weeks from date of first dose treatment; every 12 weeks after 40 week assessment; at end of treatment visit until progressive disease. Duration is approximately 3 years | 
| Time to Subsequent Antineoplastic Therapy | Time to subsequent antineoplastic therapy was defined as the time from randomization to the first date of subsequent antineoplastic therapy (excluding transplant). Participants without subsequent antineoplastic therapy were censored at the date of death or last known to be alive. | From date of last study drug to date of subsequent antineoplastic therapy, if required; approximately 3 years | 
| Plasma Concentration-time Data to Contribute to Future Population Pharmacokinetics (PK) Analysis |  | Cycle 1, Days 1 and 7; Cycle 2, Day 8; Cycle 3, Day 8; Cycle 4, Day 8. Duration is approximately 4 months. | 
| Change Form Baseline in Reported Symptoms and Quality of Life (QoL) Assessment Per Functional Assessment of Cancer Therapy-Lymphoma (FACT-LYM) for Functioning and Symptoms | The FACT-LYM includes the Functional Assessment of Cancer Therapy General Scale (FACT-G) and a 15-item lymphoma-specific subscale (LYM) over the past week. The FACT-G has 27 items that incorporate 4 scales including physical well-being (PWB; 7 items), social/family well-being (SWB, 7 items), emotional well-being (EWB; 6 items), and functional well-being (FWB; 7 items). The combined FACT-LYM instrument consists of a total of a 42 item questionnaire. Each question is answered on a 5- point scale of 0 (not at all) to 4 (very much) for a total possible score of 168. Higher scores indicate better well-being and a positive change from Baseline indicates improvement. | Baseline and End of Treatment (EOT) (Up to 152 Weeks) | 

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