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

NCT02327169 | Completed Phase 1 Results DMC FDA Drug

• 3 other identifiers: C280022014-003340-12U1111-1159-5831
• Study Type: interventional
• Target: 81
• Locations: 4 countries
• Sites: 14

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.

Conditions

Advanced Nonhematologic Malignancies

Keywords

Drug therapy

Outcome Measures

Primary Outcomes (4)

• Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

  An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment. An SAE means any untoward medical occurrence that at any dose results in death, is life-threatening, requires in patient 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.

  From Day 1, Cycle 1 through 30 days after the last dose of study drug (up to 13 months)

• Number of Participants With Dose-Limiting Toxicities (DLTs)

  DLT was defined using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 and included: any drug-related hematologic toxicity ≥Grade 4 with the exception of Grade 4 neutropenia \<7 days duration; Grade 3 or 4 neutropenia with fever \>38.5 degrees Celsius and/or infection or neutropenia requiring colony-stimulating factor OR non-hematologic DLTs that were any Grade 3, 4, or 5 toxicity with the following exceptions: Grade 3 nausea, vomiting, diarrhea, and dehydration occurring in a setting of inadequate treatment; inadequately treated hypersensitivity reactions; Grade 3 elevated transaminases or urine electrolyte abnormality ≤1 week in duration; Grade 3 serum electrolyte abnormality ≤72 hours in duration. DLTs also included: drug-related adverse experience that lead to a dose modification; unresolved drug-related toxicity resulted in delay in initiation of Cycle 2.

  From Day 1, Cycle 1 through 30 days after the last dose in Cycle 1 (up to 8 weeks)

• Maximum Tolerated Dose (MTD) for MLN2480

  Day 1, Cycle 1 up to 28 days

• Recommended Phase 2 Dose (RP2D) of MLN2480

  Day 1, Cycle 1 up to 28 days

Secondary Outcomes (17)

• Cmax : Maximum Observed Plasma Concentration for MLN2480

  Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

• Cmax: Maximum Observed Plasma Concentration for MLN0128

  Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

• Cmax: Maximum Observed Plasma Concentration for Alisertib

  Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

• Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN2480

  Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

• Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0128

  Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

Study Arms (6)

MLN2480 + MLN0128

EXPERIMENTAL

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.

Drug: MLN2480; Drug: MLN0128

MLN2480 + Alisertib

EXPERIMENTAL

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.

Drug: MLN2480; Drug: Alisertib

MLN2480 + Paclitaxel

EXPERIMENTAL

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.

Drug: MLN2480; Drug: Paclitaxel

MLN2480 + Cetuximab

EXPERIMENTAL

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.

Drug: MLN2480; Drug: Cetuximab

ML2480 + Irinotecan

EXPERIMENTAL

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.

Drug: MLN2480; Drug: Irinotecan

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

EXPERIMENTAL

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.

Drug: MLN2480

Interventions

MLN2480 DRUG

MLN2480 tablets.

Also known as: TAK-580

ML2480 + Irinotecan; MLN2480 + Alisertib; MLN2480 + Cetuximab; MLN2480 + MLN0128; MLN2480 + Paclitaxel; MLN2480 600 mg + Paclitaxel 80 mg (Dose Expansion Phase)

MLN0128 DRUG

MLN0128 capsules.

MLN2480 + MLN0128

Alisertib DRUG

Alisertib tablets.

MLN2480 + Alisertib

Paclitaxel DRUG

Paclitaxel IV infusion.

MLN2480 + Paclitaxel

Cetuximab DRUG

Cetuximab IV infusion.

MLN2480 + Cetuximab

Irinotecan DRUG

Irinotecan IV infusion.

ML2480 + Irinotecan

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• All Treatment Arms:
• Male or female participants 18 years or older.
• Participants who, in the opinion of the treating physician, have failed standard therapies and for whom a phase 1 trial is an appropriate option.
• Radiographically or clinically evaluable tumor. For expansion phase: Tumors must be measurable and of the protocol specified genetic mutational status, where applicable.
• Recovered (ie, less than or equal to \[\<=\] Grade 1 toxicity) from adverse effects (except alopecia) of prior therapy.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
• Expected survival time of at least 3 months in the opinion of the investigator.
• 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.
• Suitable vein access for the study-required blood sampling.
• 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.
• 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
• 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.
• 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.
• Participants with CRC who have received a minimum of 1 but not more than 2 prior cytotoxic-approved regimens.

You may not qualify if:

• All treatment arms:
• Female participants who are pregnant or currently breastfeeding.
• History of any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with safe protocol completion.
• 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).
• Ongoing seizure disorder or a requirement for antiepileptics.
• 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.
• Chronic therapeutic corticosteroid use with the exception of replacement therapy for adrenal insufficiency or corticosteroid inhalers.
• 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.
• Concomitant use, or administration \<= 14 days before first dose of study drug(s), of clinically significant enzyme inducers.
• Treatment with gemfibrozil (strong Cytochrome P4502C8 \[CYP2C8\] inhibitor) within 14 days before the first dose of MLN2480.
• History of or current illicit drug use, drug abuse, or alcohol abuse.
• Major surgery within 14 days before the first dose of study drug.
• Inability to comply with study requirements.
• 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.

Sponsors & Collaborators

• Millennium Pharmaceuticals, Inc.: lead

Study Sites (14)

Massachusetts General Hospital Cancer Center

Boston, Massachusetts, 2114, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 2115, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 2115, United States

Location

Fox Chase Cancer Center

Philadelphia, Pennsylvania, 19111, United States

Location

The University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Institut Bergonie

Bordeaux, Gironde, 33076, France

Location

Institut Claudius Regaud-Oncopole

Toulouse, Haute Garonne, 31059, France

Location

Institut Gustave Roussy

Villejuif, Val De Marne, 94805, France

Location

Hospital Universitari Vall d'Hebron

Barcelona, 8035, Spain

Location

START Madrid. Fundacion Jimenez Diaz

Madrid, 28040, Spain

Location

Hospital Clinico Universitario Virgen de la Victoria

Málaga, 29010, Spain

Location

Sarah Cannon Research Institure UK

London, Greater London, W1G 6AD, United Kingdom

Location

The Chrisie

Manchester, Greater Manchester, M20 4BX, United Kingdom

Location

Churchill Hospital

Oxford, Oxfordshire, OX3 7LJ, United Kingdom

Location

MeSH Terms

Interventions

tovorafenib; sapanisertib; MLN 8237; Paclitaxel; Cetuximab; Irinotecan

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Camptothecin; Alkaloids; Heterocyclic Compounds

Results Point of Contact

• Title: Takeda Study Registration Call Center
• Organization: Takeda

GlobalOncologyMedinfo@takeda.com

+1-866-835-2233

Study Officials

• Medical Director Clinical Science

  Takeda

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 23, 2014
• First Posted: December 30, 2014
• Study Start: January 14, 2015
• Primary Completion: July 2, 2018
• Study Completion: July 2, 2018
• Last Updated: February 25, 2020
• Results First Posted: February 25, 2020

Record last verified: 2020-02

Data Sharing

• IPD Sharing: Will share

Locations

ES (3); FR (3); US (5); GB (3)