Clinical trial NCT02045095: A Dose Escalation Study of MLN7243 (TAK-243) in Adult Participants With Advanced Solid Tumors
Official title: A Phase 1, Open-Label, Multicenter, Dose Escalation Study to Assess the Safety and Tolerability of MLN7243, an Inhibitor of Ubiquitin-Activating Enzyme (UAE), in Adult Patients With Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Advanced Malignant Solid Tumors
Keywords: Drug therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2014-01-24
Enrollment: 29
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate safety and tolerability (establish maximum tolerated dose \[MTD\], inform the recommended phase 2 dose \[RP2D\], and identify the dose-limiting toxicities \[DLTs\]) of MLN7243.

Detailed description: This is a single arm Phase I study with multiple dosing cohorts as noted below:

* Schedule A: MLN7243 1 mg
* Schedule A: MLN7243 2 mg
* Schedule A: MLN7243 4 mg
* Schedule A: MLN7243 8 mg
* Schedule A: MLN7243 12 mg
* Schedule A: MLN7243 18 mg
* Schedule A: MLN7243 Homozygous Mutant 4 mg

Eligibility criteria: Inclusion Criteria

Each participant must meet all of the following inclusion criteria to be enrolled in the study:

1. Male or female participants 18 years or older.
2. Participants must have a histologically confirmed diagnosis of an advanced, metastatic malignant solid tumor and must have failed or exhausted standard therapies or for which no standard therapy is available.
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
4. Participants with adequate hematologic and organ function.
5. All participants must have radiographically detectable tumors with measurable disease as defined by RECIST (version 1.1).
6. Participants undergoing a biopsy procedure must have accessible lesions which are safe to biopsy.
7. Recovered (that is, less than or equal to (\<=) Grade 1 toxicity) from the reversible effects of prior antineoplastic therapy, except alopecia.
8. Female participants who are postmenopausal for at least 1 year before the screening visit, surgically sterile, or agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 4 months after the last dose of study drug, or agree to practice true abstinence.

   Male participants who agree to practice effective barrier contraception during the entire study treatment period through 4 months after the last dose of study drug or agree to practice true abstinence.
9. Suitable venous access for the study-required blood sampling including PK sampling.

Exclusion Criteria

Participants meeting any of the following exclusion criteria are not to be enrolled in the study:

1. Participants with clinically significant pre-existing cardiac impairment.
2. Participants homozygous for the ABCG2 (BCRP) c.421C greater than (\>) 1 A polymorphism will be excluded from the study until the safety of a minimum of the first 3 dose levels has been characterized and the sponsor confirms that such participants can be enrolled at doses that are at least 3-fold lower than the most recently determined safe and tolerable dose among at least 3 dose limiting toxicities (DLT)-evaluable non-homozygous participants.
3. Participants with known active central nervous system (CNS) lesions are excluded. Systemic antineoplastic therapy or investigational agents within 21 days before the first dose of study drug.
4. Radiotherapy within 14 days before the first dose of study drug is not allowed except for limited field radiotherapy for palliative bone pain.
5. For participants where tumor biopsies are required or requested:

   * Any known coagulation abnormalities that would contraindicate the tumor biopsy procedure.
   * Ongoing therapy with any anticoagulant or antiplatelet agents (example, aspirin, clopidogrel \[Plavix®\], heparin, or warfarin).
6. Major surgery within 28 days before the first dose of MLN7243.
7. Life-threatening illness unrelated to cancer.
8. Any evidence of active infection or antibiotic therapy within 14 days before the first dose of MLN7243.
9. Known human immunodeficiency virus (HIV) positivity or AIDS-related illness, hepatitis B virus, and hepatitis C virus.
10. Participants whose weight is less than (\<) 40 kilogram (kg).
11. History of uncontrolled sleep apnea syndrome and other conditions that could result in excessive daytime sleepiness, such as severe chronic obstructive pulmonary disease.
12. Female participants who are lactating and breastfeeding or have a positive serum pregnancy test during the Screening period or a positive urine pregnancy test on Day 1 before first dose of study drug.

Primary outcomes:
measure: Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
timeFrame: Baseline up to 30 days after last dose of study drug (Cycle 10 Day 41)
measure: Number of Participants With Laboratory Related TEAEs by System Organ Class (SOC)
timeFrame: Baseline up to 30 days after last dose of study drug (Cycle 10 Day 41)
measure: Number of Participants With Vital Sign Related TEAEs by Preferred Term (PT)
timeFrame: Baseline up to 30 days after last dose of study drug (Cycle 10 Day 41)
measure: Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities
timeFrame: Cycle 1 Day 1 up to Cycle 1 Day 11
measure: Number of Participants With Clinically Significant Echocardiogram Abnormalities
timeFrame: Cycle 1 Day 2 up to 30 days after last dose of study drug (Cycle 10 Day 41)
measure: Number of Participants With TEAEs Related to Tropinin I and T
timeFrame: Baseline up to 30 days after last dose of study drug (Cycle 10 Day 41)
Secondary outcomes:
measure: Ceoi: Plasma Concentration at the End of Infusion for TAK-243
timeFrame: Cycle 1 Day 1 and 11: pre-infusion to end of infusion (up to 10 minutes)
measure: AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-243
timeFrame: Cycle 1 Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose; Cycle 1 Day 11 pre-dose and at multiple time points (up to 72 hours) post-dose
measure: AUCτ: Area Under the Plasma Concentration-time Curve Over the Dosing Interval for TAK-243
timeFrame: Cycle 1 Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose; Cycle 1 Day 11 pre-dose and at multiple time points (up to 72 hours) post-dose
measure: AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-243
timeFrame: Cycle 1 Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose; Cycle 1 Day 11 pre-dose and at multiple time points (up to 72 hours) post-dose
measure: CL: Total Clearance After Intravenous Administration for TAK-243
timeFrame: Cycle 1 Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose; Cycle 1 Day 11 pre-dose and at multiple time points (up to 72 hours) post-dose
measure: Vss: Volume of Distribution at Steady State for TAK-243
timeFrame: Cycle 1 Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose; Cycle 1 Day 11 pre-dose and at multiple time points (up to 72 hours) post-dose
measure: Aet: Amount of TAK-243 Excreted Unchanged in Urine
timeFrame: Cycle 1 Day 1; Cycle 1 Day 11
measure: Fet: Percentage of TAK-243 Excreted Unchanged in Urine
timeFrame: Cycle 1 Day 1; Cycle 1 Day 11
measure: Terminal Phase Elimination Half-life (T1/2) for TAK-243
timeFrame: Cycle 1 Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose; Cycle 1 Day 11 pre-dose and at multiple time points (up to 72 hours) post-dose
measure: Change From Baseline in Immunohistochemistry (IHC) Biomarkers in Tumor Biopsies at Cycle 1 Day 12 (C1D12) as Assessed by Histological Score (H-score)
timeFrame: Baseline and Cycle 1 Day 12
measure: Change From Baseline in IHC Biomarkers in Tumor Biopsies at C1D12 as Assessed by Positive Index
timeFrame: Baseline and Cycle 1 Day 12
measure: Percentage of Participants With Best Overall Response
timeFrame: Baseline up to end of study (approximately 7 months)
measure: Duration of Response
timeFrame: Baseline up to end of study (approximately 7 months)
Other outcomes:
Locations:
city: Boston
country: United States
state: Massachusetts
city: Saint Louis
country: United States
state: Missouri
city: Cleveland
country: United States
state: Ohio
city: Philadelphia
country: United States
state: Pennsylvania
city: Charleston
country: United States
state: South Carolina
city: Nashville
country: United States
state: Tennessee
city: San Antonio
country: United States
state: Texas
Study officials:
affiliation: Millennium Pharmaceuticals, Inc.
name: Medical Monitor
role: STUDY_DIRECTOR
References: