Clinical trial NCT00697346: Study of MLN8237 in Participants With Advanced Hematological Malignancies
Official title: An Open-label, Phase 1 Study of MLN8237, a Novel Aurora A Kinase Inhibitor, in Patients With Advanced Hematological Malignancies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
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
Keywords: Drug therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2008-06-13
Enrollment: 58
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Number of Participants With Dose-Limiting Toxicity (DLT)
timeFrame: From first dose of study drug to 30 days after the last dose (up to 422 days)
measure: Maximum Tolerated Dose (MTD) of Alisertib
timeFrame: From first dose of study drug to 30 days after the last dose (up to 422 days)
measure: Cmax: Maximum Observed Concentration for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 1
timeFrame: Cycle 1 Day 1 predose and at multiple timepoints (up to 24 hours) postdose
measure: Cmax: Maximum Observed Concentration for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21
timeFrame: Cycle 1 Day 21 predose and at multiple timepoints (up to 6 hours) postdose
measure: 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
timeFrame: Cycle 1 Day 1 predose and at multiple timepoints (up to 24 hours) postdose
measure: 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
timeFrame: Cycle 1 Day 21 predose and at multiple timepoints (up to 6 hours) postdose
measure: 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
timeFrame: Cycle 1 Day 21 predose and at multiple time points (up to 6 hours) postdose
measure: Terminal Half-Life (t1/2) for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21
timeFrame: Cycle 1 Day 21 predose and at multiple time points (up to 6 hours) postdose
measure: Accumulation Ratio (Rac) for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21
timeFrame: Cycle 1 Day 21 predose and at multiple time points (up to 6 hours) postdose
measure: Peak/Trough Ratio for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21
timeFrame: Cycle 1 Day 21 predose and at multiple timepoints (up to 6 hours) postdose
measure: 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
timeFrame: Cycle 1 Day 21 predose and at multiple timepoints (up to 6 hours) postdose
measure: Cmax: Maximum Observed Concentration for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 1
timeFrame: Cycle 1 Day 1 predose and at multiple timepoints (up to 24 hours) postdose
measure: Cmax: Maximum Observed Concentration for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 14
timeFrame: Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose
measure: 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
timeFrame: Cycle 1 Day 1 predose and at multiple timepoints (up to 24 hours) postdose
measure: 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
timeFrame: Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose
measure: 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
timeFrame: Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose
measure: Accumulation Ratio (Rac) for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 14
timeFrame: Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose
measure: Peak/Trough Ratio for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 14
timeFrame: Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose
measure: 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
timeFrame: Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose
measure: Cmax: Maximum Observed Concentration for Alisertib as Enteric Coated Tablet (ECT) With Once Daily for 14 Days (QD14D) Dosing at Day 1
timeFrame: Cycle 1 Day 1 predose and at multiple timepoints (up to 24 hours) postdose
measure: Cmax: Maximum Observed Concentration for Alisertib as Enteric Coated Tablet (ECT) With Once Daily for 14 Days (QD14D) Dosing at Day 14
timeFrame: Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose
measure: 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
timeFrame: Cycle 1 Day 1 predose and at multiple timepoints (up to 24 hours) postdose
measure: 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
timeFrame: Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose
measure: 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
timeFrame: Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose
measure: Terminal Half Life for Alisertib as Enteric Coated Tablet (ECT) With Once Daily for 14 Days (QD14D) Dosing at Day 14
timeFrame: Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose
measure: Peak/Trough Ratio for Alisertib as Enteric Coated Tablet (ECT) With Once Daily for 14 Days (QD14D) Dosing at Day 14
timeFrame: Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose
measure: 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
timeFrame: Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose
measure: Cmax: Maximum Observed Concentration for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 1
timeFrame: Cycle 1 Day 1 predose and at multiple timepoints (up to 12 hours) postdose
measure: Cmax: Maximum Observed Concentration for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7
timeFrame: Cycle 1 Day 7 predose and at multiple timepoints (up to 12 hours) postdose
measure: 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
timeFrame: Cycle 1 Day 1 predose and at multiple timepoints (up to 12 hours) postdose
measure: 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
timeFrame: Cycle 1 Day 7 predose and at multiple timepoints (up to 12 hours) postdose
measure: 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
timeFrame: Cycle 1 Days 1 predose and at multiple timepoints (up to 12 hours) postdose
measure: 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
timeFrame: Cycle 1 Day 7 predose and at multiple timepoints (up to 12 hours) postdose
measure: Terminal Half-Life (t1/2) for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7
timeFrame: Cycle 1 Day 7 predose and at multiple timepoints (up to 12 hours) postdose
measure: Accumulation Ratio (Rac) for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7
timeFrame: Cycle 1 Day 7 predose and at multiple timepoints (up to 12 hours) postdose
measure: Peak/Trough Ratio for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7
timeFrame: Cycle 1 Day 7 predose and at multiple timepoints (up to 12 hours) postdose
measure: 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
timeFrame: Cycle 1 Day 7 predose and at multiple timepoints (up to 12 hours) postdose
Secondary outcomes:
measure: Best Overall Response Rate Based on Investigator's Assessment
timeFrame: Baseline and every 2 cycles up to Month 12 until disease progression, 30 days after end of treatment (up to 422 days)
measure: Duration of Response (DOR)
timeFrame: Baseline and every 2 cycles up to Month 12 until disease progression, 30 days after end of treatment (up to 422 days)
measure: Number of Participants With Polymorphisms in Gene Encoding Enzyme UGT1A1
timeFrame: Cycle 1 Day 1 predose
measure: Number of Participants With Polymorphisms in Aurora A Kinase
timeFrame: Cycle 1 Day 1 predose
Other outcomes:
Locations:
city: Scottsdale
country: United States
state: Arizona
city: Lexington
country: United States
state: Kentucky
city: Baltimore
country: United States
state: Maryland
city: Omaha
country: United States
state: Nebraska
city: Hackensack
country: United States
state: New Jersey
city: Buffalo
country: United States
state: New York
city: Chapel Hill
country: United States
state: North Carolina
city: Nashville
country: United States
state: Tennessee
city: Houston
country: United States
state: Texas
city: San Antonio
country: United States
state: Texas
Study officials:
affiliation: Millennium Pharmaceuticals, Inc.
name: Medical Director Clinical Science
role: STUDY_DIRECTOR
References:
citation: Kelly KR, Shea TC, Goy A, Berdeja JG, Reeder CB, McDonagh KT, Zhou X, Danaee H, Liu H, Ecsedy JA, Niu H, Benaim E, Iyer SP. Phase I study of MLN8237--investigational Aurora A kinase inhibitor--in relapsed/refractory multiple myeloma, non-Hodgkin lymphoma and chronic lymphocytic leukemia. Invest New Drugs. 2014 Jun;32(3):489-99. doi: 10.1007/s10637-013-0050-9. Epub 2013 Dec 20.