Refractory Peripheral T-Cell Lymphoma, Relapsed Peripheral T-Cell Lymphoma
Conditions
Keywords
Drug Therapy
Brief summary
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
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.
Interventions
DRUGPralatrexate
Pralatrexate IV infusion
DRUGGemcitabine
Gemcitabine IV infusion
DRUGAlisertib
Alisertib enteric coated tablets
DRUGRomidepsin
Romidepsin IV infusion
Sponsors
Millennium Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) Based on Independent Review Committee (IRC) Assessment | 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 | 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. |
| Progression-Free Survival (PFS) Based on IRC Assessment | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | First dose to 30 days after last dose of study drug or comparator (Up to 152 Weeks) | Clinical laboratory tests included chemistry, hematology and urinalysis test. Clinically significant treatment-emergent laboratory abnormalities were reported by the investigator as TEAEs. |
| Number of Participants With Clinically Important Vital Sign Measurements Reported as AEs | First dose to 30 days after last dose of study drug or comparator (Up to 152 Weeks) | Vital signs included blood pressure, heart rate and temperature. Individual clinically significant changes in vital signs were reported by the investigator as TEAEs. |
| Complete Response (CR) Rate | 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) | 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. |
| Time to Disease Progression (TTP) | 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 Progression (TTP) was defined as the time from the date of randomization to the date of first documentation of PD/relapse. |
| Overall Survival (OS) | 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) | 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. |
| Time to Response | 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 is defined as the time from the date of randomization to the date of first documentation of PR or better. |
| Time to Subsequent Antineoplastic Therapy | From date of last study drug to date of subsequent antineoplastic therapy, if required; approximately 3 years | 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. |
| 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 | Baseline and End of Treatment (EOT) (Up to 152 Weeks) | 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. |
| Duration of Response (DOR) | 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 | 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. |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | First dose to 30 days after last dose of study drug or comparator (Up to 152 Weeks) | 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. |
Countries
Australia, Austria, Belarus, Belgium, Brazil, Bulgaria, Canada, Chile, Czechia, Denmark, Egypt, France, Germany, Hungary, Israel, Italy, Mexico, Netherlands, New Zealand, Peru, Poland, Portugal, Puerto Rico, Romania, Russia, Slovakia, Spain, Sweden, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at 105 investigative sites in the United States including Puerto Rico, Canada, European Union, Russian Federation, Turkey, Israel, Australia, New Zealand and Latin America from 11 June 2012 to the end of study on 18 December 2017.
Pre-assignment details
Participants with a diagnosis of Relapsed or Refractory Peripheral T-Cell Lymphoma were randomized 1:1 to either alisertib or comparator (investigator's choice of pralatrexate, romidepsin \[USA only\], or gemcitabine).
Participants by arm
| Arm | Count |
|---|---|
| Alisertib 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). | 138 |
| Pralatrexate, or Romidepsin, or Gemcitabine 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). | 133 |
| Total | 271 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 18 | 22 |
| Overall Study | Did not Receive Study Drug | 1 | 6 |
| Overall Study | Hematopoietic Stem Cell Transplant | 3 | 9 |
| Overall Study | Other Reason | 1 | 5 |
| Overall Study | Progressive Disease | 65 | 53 |
| Overall Study | Study Terminated by Sponsor | 5 | 2 |
| Overall Study | Unsatisfactory Therapeutic Response | 37 | 23 |
| Overall Study | Withdrawal by Participant | 8 | 13 |
Baseline characteristics
| Characteristic | Pralatrexate, or Romidepsin, or Gemcitabine | Alisertib | Total |
|---|---|---|---|
| Age, Continuous | 61.4 years STANDARD_DEVIATION 13.16 | 61.1 years STANDARD_DEVIATION 12.69 | 61.3 years STANDARD_DEVIATION 12.9 |
| Body Surface Area (BSA) | 1.855 m^2 STANDARD_DEVIATION 0.2562 | 1.897 m^2 STANDARD_DEVIATION 0.2465 | 1.877 m^2 STANDARD_DEVIATION 0.2517 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 21 Participants | 25 Participants | 46 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 107 Participants | 105 Participants | 212 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 8 Participants | 13 Participants |
| Height | 168.2 cm STANDARD_DEVIATION 8.99 | 170.3 cm STANDARD_DEVIATION 9.8 | 169.3 cm STANDARD_DEVIATION 9.45 |
| Race/Ethnicity, Customized Asian | 2 participants | 3 participants | 5 participants |
| Race/Ethnicity, Customized Black or African American | 8 participants | 8 participants | 16 participants |
| Race/Ethnicity, Customized Not Reported | 2 participants | 5 participants | 7 participants |
| Race/Ethnicity, Customized Other | 7 participants | 7 participants | 14 participants |
| Race/Ethnicity, Customized White | 114 participants | 115 participants | 229 participants |
| Region of Enrollment Australia | 4 participants | 5 participants | 9 participants |
| Region of Enrollment Austria | 2 participants | 2 participants | 4 participants |
| Region of Enrollment Belgium | 3 participants | 5 participants | 8 participants |
| Region of Enrollment Brazil | 10 participants | 12 participants | 22 participants |
| Region of Enrollment Bulgaria | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Canada | 0 participants | 3 participants | 3 participants |
| Region of Enrollment Czech Republic | 2 participants | 5 participants | 7 participants |
| Region of Enrollment Denmark | 2 participants | 3 participants | 5 participants |
| Region of Enrollment France | 3 participants | 5 participants | 8 participants |
| Region of Enrollment Germany | 1 participants | 6 participants | 7 participants |
| Region of Enrollment Hungary | 7 participants | 9 participants | 16 participants |
| Region of Enrollment Israel | 3 participants | 0 participants | 3 participants |
| Region of Enrollment Italy | 6 participants | 6 participants | 12 participants |
| Region of Enrollment Mexico | 1 participants | 3 participants | 4 participants |
| Region of Enrollment Netherlands | 1 participants | 0 participants | 1 participants |
| Region of Enrollment New Zealand | 2 participants | 3 participants | 5 participants |
| Region of Enrollment Peru | 3 participants | 1 participants | 4 participants |
| Region of Enrollment Poland | 3 participants | 7 participants | 10 participants |
| Region of Enrollment Portugal | 1 participants | 1 participants | 2 participants |
| Region of Enrollment Puerto Rico | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Romania | 1 participants | 2 participants | 3 participants |
| Region of Enrollment Russia | 4 participants | 4 participants | 8 participants |
| Region of Enrollment Spain | 11 participants | 14 participants | 25 participants |
| Region of Enrollment Sweden | 3 participants | 0 participants | 3 participants |
| Region of Enrollment Turkey | 11 participants | 10 participants | 21 participants |
| Region of Enrollment United Kingdom | 8 participants | 3 participants | 11 participants |
| Region of Enrollment United States | 39 participants | 29 participants | 68 participants |
| Sex: Female, Male Female | 47 Participants | 46 Participants | 93 Participants |
| Sex: Female, Male Male | 86 Participants | 92 Participants | 178 Participants |
| Weight | 74.63 kg STANDARD_DEVIATION 19.601 | 76.85 kg STANDARD_DEVIATION 17.242 | 75.76 kg STANDARD_DEVIATION 18.437 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 11 / 137 | 5 / 29 | 8 / 76 | 2 / 22 |
| other Total, other adverse events | 134 / 137 | 29 / 29 | 72 / 76 | 21 / 22 |
| serious Total, serious adverse events | 75 / 137 | 18 / 29 | 46 / 76 | 6 / 22 |
Outcome results
Primary
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.
Time frame: 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
Population: Response-evaluable population, participants with peripheral T-cell lymphoma confirmed by an independent hematopathology central review, with measurable disease at Baseline, who received at least 1 dose of alisertib or comparator and had postbaseline response assessment of CR, PR, stable disease (SD) or progressive disease (PD) by the IRC.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alisertib | Overall Response Rate (ORR) Based on Independent Review Committee (IRC) Assessment | 33 percentage of participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Overall Response Rate (ORR) Based on Independent Review Committee (IRC) Assessment | 45 percentage of participants |
p-value: 0.03895% CI: [0.33, 1.08]Cochran-Mantel-Haenszel
Primary
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.
Time frame: 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
Population: Intent-to-treat (ITT) population was defined as all participants who were randomized. The participants were analyzed according to the treatment they were randomized to receive, regardless of any errors of dosing.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alisertib | Progression-Free Survival (PFS) Based on IRC Assessment | 115 days |
| Pralatrexate, or Romidepsin, or Gemcitabine | Progression-Free Survival (PFS) Based on IRC Assessment | 104 days |
p-value: 0.17795% CI: [0.637, 1.178]Stratified Log Rank
Secondary
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.
Time frame: Baseline and End of Treatment (EOT) (Up to 152 Weeks)
Population: ITT population was defined as all participants who were randomized. The participants were analyzed according to the treatment they were randomized to receive, regardless of any errors of dosing.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib | 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 | Physical Well-Being, EOT | -2.4 score on a scale | Standard Deviation 6.21 |
| Alisertib | 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 | Social/Family Well-Being, EOT | -0.3 score on a scale | Standard Deviation 4.5 |
| Alisertib | 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 | Emotional Well-Being, EOT | -1.4 score on a scale | Standard Deviation 4.59 |
| Alisertib | 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 | Functional Well-Being, EOT | -2.4 score on a scale | Standard Deviation 5.4 |
| Pralatrexate, or Romidepsin, or Gemcitabine | 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 | Functional Well-Being, EOT | -0.3 score on a scale | Standard Deviation 4.79 |
| Pralatrexate, or Romidepsin, or Gemcitabine | 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 | Physical Well-Being, EOT | -1.3 score on a scale | Standard Deviation 5.27 |
| Pralatrexate, or Romidepsin, or Gemcitabine | 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 | Emotional Well-Being, EOT | -0.8 score on a scale | Standard Deviation 3.93 |
| Pralatrexate, or Romidepsin, or Gemcitabine | 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 | Social/Family Well-Being, EOT | 0.0 score on a scale | Standard Deviation 4.44 |
Secondary
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.
Time frame: 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)
Population: Response-evaluable population was defined as participants with peripheral T-cell lymphoma confirmed by an independent hematopathology central review, with measurable disease at baseline, who receive at least 1 dose of alisertib or the comparator drug, and 1 postbaseline response assessment of CR, PR, SD or PD by the independent radiology committee.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alisertib | Complete Response (CR) Rate | 18 percentage of participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Complete Response (CR) Rate | 27 percentage of participants |
Secondary
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.
Time frame: 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
Population: All responders in response-evaluable population defined as participants with peripheral T-cell lymphoma confirmed by independent hematopathology central review with measurable disease at baseline who receive at least 1 dose of alisertib or comparator drug and 1 postbaseline response assessment of CR, PR, SD or PD by independent radiology committee.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alisertib | Duration of Response (DOR) | 225 days |
| Pralatrexate, or Romidepsin, or Gemcitabine | Duration of Response (DOR) | 172 days |
Secondary
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.
Time frame: First dose to 30 days after last dose of study drug or comparator (Up to 152 Weeks)
Population: Safety population was defined as all participants who received at least 1 dose of alisertib, or one of the comparator drugs. Participants were analyzed according to the treatment actually received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alisertib | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Liver Function Test Abnormal | 0 participants |
| Alisertib | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Neutrophil Count Decreased | 18 participants |
| Alisertib | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | White Blood Cell Count Decreased | 17 participants |
| Alisertib | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Lymphocyte Count Decreased | 6 participants |
| Alisertib | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Monocyte Count Decreased | 2 participants |
| Alisertib | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Lymphocyte Count Increased | 1 participants |
| Alisertib | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Monocyte Count Increased | 1 participants |
| Alisertib | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | White Blood Cell Count Increased | 1 participants |
| Alisertib | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Platelet Count Decreased | 15 participants |
| Alisertib | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Alanine Aminotransferase Increased | 8 participants |
| Alisertib | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Aspartate Aminotransferase Increased | 5 participants |
| Alisertib | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Gamma-glutamyltransferase Increased | 6 participants |
| Alisertib | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Blood Bilirubin Increased | 2 participants |
| Alisertib | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Hepatic Enzyme Increased | 2 participants |
| Alisertib | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Transaminases Increased | 0 participants |
| Alisertib | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Blood Alkaline Phosphatase Increased | 9 participants |
| Alisertib | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Blood Lactate Dehydrogenase Increased | 5 participants |
| Alisertib | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Blood Creatinine Increased | 3 participants |
| Alisertib | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Blood Creatinine Decreased | 0 participants |
| Alisertib | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Blood Urea Increased | 1 participants |
| Alisertib | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Blood Potassium Decreased | 1 participants |
| Alisertib | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Blood Magnesium Decreased | 1 participants |
| Alisertib | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Blood Bicarbonate Decreased | 0 participants |
| Alisertib | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Blood Calcium Decreased | 0 participants |
| Alisertib | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Blood Calcium Increased | 1 participants |
| Alisertib | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Blood Phosphorus Decreased | 0 participants |
| Alisertib | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Calcium Ionised Increased | 1 participants |
| Alisertib | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Haemoglobin Decreased | 1 participants |
| Alisertib | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Haematocrit Increased | 1 participants |
| Alisertib | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Haematocrit Decreased | 1 participants |
| Alisertib | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Coagulation Factor XIII Level Decreased | 1 participants |
| Alisertib | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | International Normalised Ratio Increased | 1 participants |
| Alisertib | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Blood Albumin Decreased | 0 participants |
| Alisertib | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Myocardial Necrosis Marker Increased | 1 participants |
| Alisertib | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Troponin Increased | 0 participants |
| Alisertib | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Blood Glucose Increased | 0 participants |
| Alisertib | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Immunoglobulins Increased | 1 participants |
| Alisertib | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Blood Uric Acid Increased | 1 participants |
| Alisertib | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Enterovirus Test Positive | 0 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Blood Urea Increased | 0 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Haematocrit Decreased | 0 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Neutrophil Count Decreased | 14 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Blood Potassium Decreased | 4 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | White Blood Cell Count Decreased | 10 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Troponin Increased | 1 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Lymphocyte Count Decreased | 5 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Blood Magnesium Decreased | 2 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Monocyte Count Decreased | 1 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Coagulation Factor XIII Level Decreased | 0 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Lymphocyte Count Increased | 0 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Blood Bicarbonate Decreased | 1 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Monocyte Count Increased | 0 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Enterovirus Test Positive | 1 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | White Blood Cell Count Increased | 0 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Blood Calcium Decreased | 1 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Platelet Count Decreased | 22 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | International Normalised Ratio Increased | 0 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Alanine Aminotransferase Increased | 11 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Blood Calcium Increased | 0 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Aspartate Aminotransferase Increased | 11 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Blood Glucose Increased | 1 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Gamma-glutamyltransferase Increased | 3 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Blood Phosphorus Decreased | 1 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Blood Bilirubin Increased | 1 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Blood Albumin Decreased | 2 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Hepatic Enzyme Increased | 0 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Liver Function Test Abnormal | 1 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Calcium Ionised Increased | 0 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Transaminases Increased | 1 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Blood Uric Acid Increased | 0 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Blood Alkaline Phosphatase Increased | 7 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Haemoglobin Decreased | 3 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Blood Lactate Dehydrogenase Increased | 1 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Myocardial Necrosis Marker Increased | 0 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Blood Creatinine Increased | 7 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Haematocrit Increased | 2 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Blood Creatinine Decreased | 1 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Abnormal Laboratory Values Reported as AEs | Immunoglobulins Increased | 0 participants |
Secondary
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.
Time frame: First dose to 30 days after last dose of study drug or comparator (Up to 152 Weeks)
Population: Safety population was defined as all participants who received at least 1 dose of alisertib, or one of the comparator drugs. Participants were analyzed according to the treatment actually received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alisertib | Number of Participants With Clinically Important Vital Sign Measurements Reported as AEs | Heart Rate Increased | 1 participants |
| Alisertib | Number of Participants With Clinically Important Vital Sign Measurements Reported as AEs | Body Temperature Increased | 0 participants |
| Alisertib | Number of Participants With Clinically Important Vital Sign Measurements Reported as AEs | Hypotension | 4 participants |
| Alisertib | Number of Participants With Clinically Important Vital Sign Measurements Reported as AEs | Orthostatic Hypotension | 2 participants |
| Alisertib | Number of Participants With Clinically Important Vital Sign Measurements Reported as AEs | Hypertension | 5 participants |
| Alisertib | Number of Participants With Clinically Important Vital Sign Measurements Reported as AEs | Pyrexia | 48 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Vital Sign Measurements Reported as AEs | Hypertension | 7 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Vital Sign Measurements Reported as AEs | Heart Rate Increased | 0 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Vital Sign Measurements Reported as AEs | Orthostatic Hypotension | 1 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Vital Sign Measurements Reported as AEs | Body Temperature Increased | 1 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Vital Sign Measurements Reported as AEs | Pyrexia | 40 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Clinically Important Vital Sign Measurements Reported as AEs | Hypotension | 6 participants |
Secondary
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.
Time frame: First dose to 30 days after last dose of study drug or comparator (Up to 152 Weeks)
Population: Safety population was defined as all participants who received at least 1 dose of alisertib, or one of the comparator drugs. Participants were analyzed according to the treatment actually received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alisertib | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAE | 136 participants |
| Alisertib | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAE | 75 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAE | 126 participants |
| Pralatrexate, or Romidepsin, or Gemcitabine | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAE | 69 participants |
Secondary
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.
Time frame: 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)
Population: ITT population was defined as all participants who were randomized. The participants were analyzed according to the treatment they were randomized to receive, regardless of any errors of dosing.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alisertib | Overall Survival (OS) | 415 days |
| Pralatrexate, or Romidepsin, or Gemcitabine | Overall Survival (OS) | 367 days |
p-value: 0.33895% CI: [0.707, 1.369]Stratified Log-rank Test
Secondary
Plasma Concentration-time Data to Contribute to Future Population Pharmacokinetics (PK) Analysis
Time frame: Cycle 1, Days 1 and 7; Cycle 2, Day 8; Cycle 3, Day 8; Cycle 4, Day 8. Duration is approximately 4 months.
Population: This Outcome Measure was registered in error and is not a Primary or Secondary Outcome Measure.
Secondary
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.
Time frame: 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
Population: ITT population was defined as all participants who were randomized. The participants were analyzed according to the treatment they were randomized to receive, regardless of any errors of dosing.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alisertib | Time to Disease Progression (TTP) | 162 days |
| Pralatrexate, or Romidepsin, or Gemcitabine | Time to Disease Progression (TTP) | 116 days |
p-value: 0.36295% CI: [0.679, 1.329]Stratified Log Rank
Secondary
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.
Time frame: 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
Population: All responders in response-evaluable population defined as participants with peripheral T-cell lymphoma confirmed by independent hematopathology central review with measurable disease at baseline who receive at least 1 dose of alisertib or comparator drug and 1 postbaseline response assessment of CR, PR, SD or PD by independent radiology committee.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alisertib | Time to Response | 62 days |
| Pralatrexate, or Romidepsin, or Gemcitabine | Time to Response | 64 days |
Secondary
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.
Time frame: From date of last study drug to date of subsequent antineoplastic therapy, if required; approximately 3 years
Population: ITT population was defined as all participants who were randomized. The participants were analyzed according to the treatment they were randomized to receive, regardless of any errors of dosing.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alisertib | Time to Subsequent Antineoplastic Therapy | 336 days |
| Pralatrexate, or Romidepsin, or Gemcitabine | Time to Subsequent Antineoplastic Therapy | 233 days |