Study of MLN2480 in Participants With Relapsed or Refractory Solid Tumors Followed by a Dose Expansion in Participants With Metastatic Melanoma

NCT01425008 | Completed Phase 1 Results FDA Drug

• 4 other identifiers: C280012012-003397-16U1111-1164-750813/SC/0007
• Study Type: interventional
• Target: 149
• Locations: 2 countries
• Sites: 16

Brief Summary

This is a phase 1, multicenter, nonrandomized, open-label, dose escalation study. The study will be conducted in 2 stages, Dose Escalation and Dose Expansion. The Dose Escalation phase will include participants with solid tumors (including melanoma) who have failed or are not candidates for standard therapies or for whom no approved therapy is available. The Dose Expansion phase will include participants with metastatic melanoma.

Conditions

Melanoma; Metastatic Melanoma; Solid Tumor; Neoplasm

Keywords

Drug Therapy

Outcome Measures

Primary Outcomes (7)

• Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Deaths

  Baseline up to 30 days after last dose, or start of subsequent therapy, whichever occurred first (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle=22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle=28 days] in Expansion Phase)

• Dose Escalation Phase: Number of Participants With Dose-limiting Adverse Events (AEs)

  Dose limiting AEs were evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. Dose limiting AEs were defined as any of the following events: Grade 4 neutropenia for more than 7 days under maximum supportive therapy; febrile neutropenia; platelet counts decreased of Grade 3 requiring platelet transfusion or blood platelet decreased of Grade 4; if Course 2 was not initiated within 14 days due to AE related to the protocol treatment; Grade 3 or higher non-hematologic toxicity that was considered clinically significant, except the following cases, Grade 3 gastrointestinal symptoms that could be controlled with supportive therapy (example, appropriate use of antiemetics, antidiarrheals), and Grade 3 or higher electrolyte abnormalities that were not deemed clinically significant.

  Cycle 1 (Cycle length= 22 days [Q2D] and 28 days [QW])

• Number of Participants With TEAEs Related to Physical Examination Findings

  Baseline up to 30 days after last dose, or start of subsequent therapy, whichever occurred first (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle=22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle=28 days] in Expansion Phase)

• Clinically Significant Change From Baseline in Body Weight at End of Study Visit (EOSV)

  Baseline up to EOSV (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle length =22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle length =28 days] in Expansion Phase)

• Number of Participants With Abnormal Clinically Significant Electrocardiogram (ECG) Findings

  Baseline up to 30 days after last dose, or start of subsequent therapy, whichever occurred first (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle=22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle=28 days] in Expansion Phase)

• Eastern Cooperative Oncology Group (ECOG) Performance Score

  ECOG performance score was measured on 6 point scale to assess participant's performance status, where: 0 (fully active, able to carry on all pre-disease activities without restriction); 1 (restricted in physically strenuous activity, but ambulatory and able to carry out light or sedentary work); 2 (ambulatory greater than(\>) 50 percent (%) of waking hours), capable of all self-care, unable to carry out any work activities); 3 (capable of only limited self-care, confined to bed or chair \>50% of waking hours); 4(completely disabled, cannot carry on any self-care, totally confined to bed or chair); 5 (dead). A higher score indicated greater functional impairment.

  at EOSV (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle length =22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle length =28 days] in Expansion Phase)

• Number of Participants With TEAEs Categorized Into Investigations Related to Laboratory Test of Chemistry, Hematology or Urinalysis

  Baseline up to 30 days after last dose, or start of subsequent therapy, whichever occurred first (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle=22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle=28 days] in Expansion Phase)

Secondary Outcomes (12)

• Overall Response Rate (ORR)

  Baseline up to EOSV (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle length =22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle length =28 days] in Expansion Phase)

• Progression-free Survival (PFS)

  Baseline up to the date of first document PD, or death due to any cause, whichever occurred first (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle =22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle =28 days] in Expansion Phase)

• Duration of Response (DOR)

  From the first documented response (CR or PR) up to the date of first documented PD (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle =22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle =28 days] in Expansion Phase)

• Dose Escalation Phase and Dose Expansion Pharmacokinetic Cohort, Cmax: Maximum Observed Plasma Concentration for TAK-580

  Escalation (Esc.) and Expansion (Exp.) Q2D: C1D1 and 21 pre-dose and at multiple time points (up to 48 hours [h]) post-dose (C=22 days [Esc. Q2D] and 28 days [Exp. Q2D]); Esc. QW: C1D1 and 22 at multiple time-points (up to168 h) post-dose (C=28 days)

• Dose Escalation Phase and Dose Expansion Pharmacokinetic Cohort, Ctrough: Trough Concentration for TAK-580

  Escalation and Expansion Q2D Cohorts: C1D21 pre-dose (C=22 days [Escalation Q2D] and 28 days [Expansion Q2D]); Escalation QW Cohorts: C1D22 pre-dose (C= 28 days)

Study Arms (1)

MLN2480

EXPERIMENTAL

Drug: MLN2480

Interventions

MLN2480 DRUG

Dose Escalation Phase: participants will receive MLN2480 orally in escalating doses every other day or once weekly for three weeks of a 28-day cycle. Participants may continue treatment for additional cycles (up to 12 months) until disease progression, unacceptable toxicity, or the participant discontinues for any other reason. If it is determined that a participant would derive benefit from continued therapy beyond 12 months treatment may continue. Dose Expansion Phase: Participants will take MLN2480 at the maximum tolerated dose orally every other day or once weekly for three weeks of a 28-day cycle until disease progression, unacceptable toxicity, or the participant discontinues for any other reason. The maximum duration of treatment is 1 year unless determined that a participant would derive benefit from continued therapy beyond 12 months.

Also known as: TAK-580

MLN2480

Eligibility Criteria

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

You may qualify if:

• Informed consent.
• Male or female participants 18 years or older.
• Dose Escalation phase: Participants with solid tumors (including melanoma) who have failed or are not candidates for standard therapies of for whom no approved therapy is available.
• Dose Expansion phase: Metastatic melanoma (locally advanced or metastatic melanoma).
• Dose Expansion phase: At least 1 measurable lesion which has not been treated previously with radiotherapy. A newly arising lesion in a previously irradiated field is acceptable.
• For participants undergoing biopsy procedures: Prothrombin time (PT) and activated partial thromboplastin time (aPTT) must be within the normal range.
• Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to (\<=) 1.
• Adequate tissue sample from either archival formalin-fixed paraffin-embedded (FFPE) tumor tissue or new biopsy of tumor.
• Previous chemotherapy, immunotherapy, and hormone therapy must be completed at least 4 weeks prior to the administration of MLN2480 and radiation must be completed at least 3 weeks prior to the administration of MLN2480; all associated toxicity must be resolved to \<=Grade 1.
• Expected survival time of at least 3 months in the opinion of the investigator.
• Participants who do not have hypo- or hyperthyroidism.
• Ability to swallow and retain oral medication.
• Female participants who are postmenopausal for at least 1 year, surgically sterile, or agree to practice 2 effective methods of contraception through 3 months after the last dose of study drug or agree to practice true abstinence.
• Male participants who, even if surgically sterilized, agree to practice effective barrier contraception through 3 months after the last dose of alisertib or agree to practice true abstinence.

You may not qualify if:

• History of any major disease that might interfere with safe protocol participation.
• Dose Expansion phase: Previous treatment with RAF or MEK inhibitors.
• Laboratory values as specified in study protocol.
• Current enrollment in any other investigational treatment study.
• Evidence of current uncontrolled cardiovascular conditions within the past 6 months.
• Prior investigational agents for malignant or non-malignant disease within 4 weeks prior to Day 1.
• Active hepatitis or human immunodeficiency virus (HIV) infection.
• Active bacterial or viral infection.
• Female participants who are pregnant or currently breastfeeding.
• Major surgery within 28 days of Day 1.
• Refractory nausea and vomiting, malabsorption, or significant bowel or stomach resection.
• Inability to comply with study requirements.
• Other unspecified reasons that, in the opinion of the investigator or Millennium, make the participant unsuitable for enrollment.

Sponsors & Collaborators

• Millennium Pharmaceuticals, Inc.: lead

Study Sites (16)

Unknown Facility

San Francisco, California, United States

Location

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Denver, Colorado, United States

Location

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Augusta, Georgia, United States

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Indianapolis, Indiana, United States

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New York, New York, United States

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Easton, Pennsylvania, United States

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Philadelphia, Pennsylvania, United States

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San Antonio, Texas, United States

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Lakewood, Washington, United States

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Bristol, Avon, United Kingdom

Location

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Cambridge, Cambridgeshire, United Kingdom

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Chelmsford, Essex, United Kingdom

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London, Greater London, United Kingdom

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Manchester, Greater Manchester, United Kingdom

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Unknown Facility

Oxford, Oxfordshire, United Kingdom

Location

Unknown Facility

Newcastle upon Tyne, Tyne & Wear, United Kingdom

Location

Related Publications (1)

• Rasco DW, Medina T, Corrie P, Pavlick AC, Middleton MR, Lorigan P, Hebert C, Plummer R, Larkin J, Agarwala SS, Daud AI, Qiu J, Bozon V, Kneissl M, Barry E, Olszanski AJ. Phase 1 study of the pan-RAF inhibitor tovorafenib in patients with advanced solid tumors followed by dose expansion in patients with metastatic melanoma. Cancer Chemother Pharmacol. 2023 Jul;92(1):15-28. doi: 10.1007/s00280-023-04544-5. Epub 2023 May 23.

  PMID: 37219686 DERIVED

MeSH Terms

Conditions

Melanoma; Neoplasms

Interventions

tovorafenib

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Results Point of Contact

• Title: Medical Director
• Organization: Takeda

trialdisclosures@takeda.com

+1-877-825-3327

Study Officials

• Medical Monitor

  Millennium Pharmaceuticals, Inc.

  STUDY DIRECTOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 26, 2011
• First Posted: August 29, 2011
• Study Start: September 15, 2011
• Primary Completion: April 11, 2017
• Study Completion: October 16, 2018
• Last Updated: August 10, 2020
• Results First Posted: August 10, 2020

Record last verified: 2020-07

Data Sharing

• IPD Sharing: Will share

Locations

US (9); GB (7)