A Study MLN2480 in Combination With MLN0128 or Alisertib, or Paclitaxel, or Cetuximab, or Irinotecan in Adult Participants With Advanced Nonhematologic Malignancies

NCT ID: NCT02327169

Last Updated: 2020-02-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 81 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-01-14
• Study Completion Date: 2018-07-02

Brief Summary

The primary purpose of this study is to determine the safety profile and the maximum tolerated doses (MTDs)/ potential recommended phase 2 doses (RP2Ds) of the combination treatments of MLN2480 + MLN0128, MLN2480 + alisertib, MLN2480 + paclitaxel, MLN2480 + cetuximab, and MLN2480 + irinotecan in participants with advanced nonhematologic malignancies.

Detailed Description

The drug being tested in this study is called MLN2480 (TAK-580). MLN2480 was tested to evaluate side effects and determine the maximum tolerated dose (MTD) and recommended dose for future studies when administered in combination with five other medications. This study was to assess the safety of MLN2480 as well as how it is processed by the body in participants with solid nonhematologic malignancies who have failed standard therapies.

The study was to be conducted in two phases, the dose escalation phase and the dose expansion phase. A total of 71 participants were enrolled in the escalation phase. Participants in this phase were assigned to one of the five treatment groups:

• MLN2480 + MLN0128
• MLN2480 + Alisertib
• MLN2480 + Paclitaxel
• MLN2480 + Cetuximab
• MLN2480 + Irinotecan

Once the MTD for each combination treatment arm was established in the escalation phase, one or more of the combination treatments will be selected for the expansion phase. A total of 10 participants were enrolled in the expansion phase.

This multi-centre trial was be conducted worldwide. The overall time to participate in this study is approximately 14 months. Participants made multiple visits to the clinic including an end of study visit 30 days after last dose of study drug for a follow-up assessment.

Conditions

Advanced Nonhematologic Malignancies

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

MLN2480 + MLN0128

Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles.

Group Type: EXPERIMENTAL

MLN2480

Intervention Type: DRUG

MLN2480 tablets.

MLN0128

Intervention Type: DRUG

MLN0128 capsules.

MLN2480 + Alisertib

Dose Escalation Phase: MLN2480 100-200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30-40 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.

Group Type: EXPERIMENTAL

MLN2480

Intervention Type: DRUG

MLN2480 tablets.

Alisertib

Intervention Type: DRUG

Alisertib tablets.

MLN2480 + Paclitaxel

Dose Escalation Phase: MLN2480 100-200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 milligram per square meter (mg/m\^2), intravenous (IV) infusion, once weekly (QW) for 3 weeks in each 28-day cycle for up to 12 cycles or MLN2480 400-600 mg tablets, orally, QW on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m\^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care.

Group Type: EXPERIMENTAL

MLN2480

Intervention Type: DRUG

MLN2480 tablets.

Paclitaxel

Intervention Type: DRUG

Paclitaxel IV infusion.

MLN2480 + Cetuximab

Dose Escalation Phase: MLN2480 400-600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m\^2 (cycle 1 Day 1), then at 250 mg/m\^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care.

Group Type: EXPERIMENTAL

MLN2480

Intervention Type: DRUG

MLN2480 tablets.

Cetuximab

Intervention Type: DRUG

Cetuximab IV infusion.

ML2480 + Irinotecan

Dose Escalation Phase: MLN2480 400-600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m\^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care.

Group Type: EXPERIMENTAL

MLN2480

Intervention Type: DRUG

MLN2480 tablets.

Irinotecan

Intervention Type: DRUG

Irinotecan IV infusion.

MLN2480 600 mg + Paclitaxel 80 mg (Dose Expansion Phase)

Dose Expansion Phase: MLN2480 600 mg, tablets, orally, once per week on Days 2, 9, 16 and 23 of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg, capsules, orally, once on 1, 8, and 15 of a 28-day cycle for up to 12 cycles.

Group Type: EXPERIMENTAL

MLN2480

Intervention Type: DRUG

MLN2480 tablets.

Interventions

MLN2480

MLN2480 tablets.

Intervention Type: DRUG

MLN0128

MLN0128 capsules.

Intervention Type: DRUG

Alisertib

Alisertib tablets.

Intervention Type: DRUG

Paclitaxel

Paclitaxel IV infusion.

Intervention Type: DRUG

Cetuximab

Cetuximab IV infusion.

Intervention Type: DRUG

Irinotecan

Irinotecan IV infusion.

Intervention Type: DRUG

Other Intervention Names

TAK-580

Eligibility Criteria

Inclusion Criteria

All Treatment Arms:

1. Male or female participants 18 years or older.

2. Participants who, in the opinion of the treating physician, have failed standard therapies and for whom a phase 1 trial is an appropriate option.

3. Radiographically or clinically evaluable tumor. For expansion phase: Tumors must be measurable and of the protocol specified genetic mutational status, where applicable.

4. Recovered (ie, less than or equal to [<=] Grade 1 toxicity) from adverse effects (except alopecia) of prior therapy.

5. Eastern Cooperative Oncology Group (ECOG) performance status 0-1.

6. Expected survival time of at least 3 months in the opinion of the investigator.

7. Block of banked tumor tissue and/or greater than or equal to (>=) 10 unstained slides. Participants who satisfy all other eligibility criteria but do not have banked tissue/slides may be asked to consent to baseline biopsy.

8. Suitable vein access for the study-required blood sampling.

9. Thyroid function tests consistent with stable thyroid function. Note: Participants on a stable dose of thyroid replacement therapy for a suggested minimum of 12 weeks before Cycle 1, Day 1 are eligible.

10. Left ventricular ejection fraction (LVEF) of 50 percent (%) or greater, as measured by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA), within 28 days before the first dose of MLN2480

11. Female participants who are post-menopausal for at least 1 year, surgically sterile, or agree to practice 2 effective methods of contraception through 120 days (4 months) after the last dose of study drug for participants in Arms 1, 2, and 5, and through 6 months for participants in Arms 3 and 4, or agree to practice true abstinence.

12. Male participants who, even if surgically sterilized, agree to practice effective barrier contraception through 120 days (4 months) after the last dose of study drug for participants in Arms 1, 2, and 5, and through 6 months for participants in Arms 3, and 4, or agree to practice true abstinence.

a. Participants with Kirsten rat sarcoma viral oncogene homolog (KRAS) exon 2 or BRAF non-V600 mutation-positive non-small cell lung cancer (NSCLC) who have received a minimum of 1 but not more than 2 prior cytotoxic-approved regimens.

1. Participants with CRC who have received a minimum of 1 but not more than 2 prior cytotoxic-approved regimens.

Exclusion Criteria

All treatment arms:

1. Female participants who are pregnant or currently breastfeeding.

2. History of any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with safe protocol completion.

3. History of uncontrolled brain metastasis unless: previously treated with surgery, whole-brain radiation, or stereotactic radiosurgery; stable disease for >= 60 days without steroid use (or stable steroid dose established for >= 28 days before the first dose of MLN2480).

4. Ongoing seizure disorder or a requirement for antiepileptics.

5. Recent prior therapies, including: chemotherapy and hormonal therapy <= 4 weeks or 4 half lives, whichever occurs first, before administration of study drug; immunotherapy/monoclonal antibody use <= 4 weeks before administration of MLN2480; or radiation therapy <= 3 weeks before administration of study drug.

6. Chronic therapeutic corticosteroid use with the exception of replacement therapy for adrenal insufficiency or corticosteroid inhalers.

7. Known history of human immunodeficiency virus infection, hepatitis B, or hepatitis C; Prior allogeneic bone marrow or organ transplantation, or active condition of chronic immune suppression is not allowed.

8. Concomitant use, or administration <= 14 days before first dose of study drug(s), of clinically significant enzyme inducers.

9. Treatment with gemfibrozil (strong Cytochrome P4502C8 [CYP2C8] inhibitor) within 14 days before the first dose of MLN2480.

10. History of or current illicit drug use, drug abuse, or alcohol abuse.

11. Major surgery within 14 days before the first dose of study drug.

12. Inability to comply with study requirements.

13. Other unspecified reasons that, in the opinion of the investigator or Millennium, make the participant unsuitable for enrollment.

a. Prior treatment with rapidly accelerated fibrosarcoma (RAF), extracellular signal-regulated kinases (MEK), or other inhibitors of the mitogen-activated protein kinase (MAPK) pathway.

a. History of uncontrolled sleep apnea syndrome and other conditions that could result in excessive daytime sleepiness, such as severe chronic obstructive pulmonary disease.

a. Known hypersensitivity to paclitaxel, or its components or other drugs formulated in Cremophor® EL (polyoxyethylated castor oil).

1. Use of strong or moderate Cytochrome P4503A (CYP3A) inhibitors <= days of the first dose of irinotecan.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Millennium Pharmaceuticals, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Director Clinical Science

Role: STUDY_DIRECTOR

Takeda

Locations

Massachusetts General Hospital Cancer Center

Boston, Massachusetts, United States

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States

Dana Farber Cancer Institute

Boston, Massachusetts, United States

Fox Chase Cancer Center

Philadelphia, Pennsylvania, United States

The University of Texas MD Anderson Cancer Center

Houston, Texas, United States

Institut Bergonie

Bordeaux, Gironde, France

Institut Claudius Regaud-Oncopole

Toulouse, Haute Garonne, France

Institut Gustave Roussy

Villejuif, Val De Marne, France

Hospital Universitari Vall d'Hebron

Barcelona, , Spain

START Madrid. Fundacion Jimenez Diaz

Madrid, , Spain

Hospital Clinico Universitario Virgen de la Victoria

Málaga, , Spain

Sarah Cannon Research Institure UK

London, Greater London, United Kingdom

The Chrisie

Manchester, Greater Manchester, United Kingdom

Churchill Hospital

Oxford, Oxfordshire, United Kingdom

Countries

United States; France; Spain; United Kingdom

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

2014-003340-12

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

U1111-1159-5831

Identifier Type: OTHER

Identifier Source: secondary_id

C28002

Identifier Type: -

Identifier Source: org_study_id