NCT00697346 - Study of MLN8237 in Participants With Advanced Hematological Malignancies | Crick

Eligibility

Sex: ALLMin age: 18 Years

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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

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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