A Phase I/II Study of MLN0128 in Metastatic Anaplastic Thyroid Cancer and Incurably Poorly Differentiated or Radioidodine Refractory Differentiated Thyroid Cancer

Phase 1

Completed

• Conditions: Anaplastic Thyroid Cancer; Thyroid Cancer; Differentiated Thyroid Cancer
• Interventions: Drug: MLN0128

• Registration Number: NCT02244463
• Lead Sponsor: Dana-Farber Cancer Institute

Brief Summary

This research study is a phase I/II study of MLN0128 in metastatic anaplastic thyroid cancer(ATC) and incurably poorly differentiated or radioidodine refractory differentiated thyroid cancer (DTC).

Due to changes in the manufacturing process which resulted in increased absorption of MLN0128 from capsules, a run-in phase I prior to the phase II of the study was needed.

Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that the intervention is being studied. The FDA (the U.S. Food and Drug Administration) has not approved MLN0128 as a treatment for any disease.

MLN0128 prevents tumor cells from dividing and growing by selectively and potently inhibiting a chemical, mTOR kinase, which regulates cell growth and survival. Patients with anaplastic thyroid cancer have been observed to sometimes carry genetic alterations in their tumor cells which may make the cancer more sensitive to inhibition by MLN0128.

Given the activity with everolimus in RAI refractory thyroid cancer, subjects wth metastatic, incurable differentiated RAI refractory and poorly differentiated thyroid cancer were included.

Detailed Description

Patients who fulfill eligibility criteria will be entered into the trial to receive MLN0128.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2014-09-17
• Study First Submitted QC: 2014-09-17
• Study First Posted: 2014-09-19
• Study Start: 2015-07
• Primary Completion: 2022-04-28
• Study Completion: 2022-04-28
• Results First Submitted: 2023-04-06
• Status Verified: 2023-12
• Results First Submitted QC: 2023-12-15
• Last Update Submitted: 2023-12-15
• Results First Posted: 2024-01-12
• Last Update Posted: 2024-01-12

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 46

Inclusion Criteria

• Male or female patients 18 years or older

• Any number of prior chemotherapy or targeted agents including rapamycin analogues allowed

• Newly diagnosed or refractory/metastatic anaplastic thyroid cancer confirmed by histology, incurable by surgery, radiotherapy or chemoradiotherapy alone or in combination

• Must have measurable disease

• ECOG performance status 0-2

• No active intracranial metastases

• Tissue for correlative studies must be available

• Ability to swallow oral medications

• Voluntary written consent must be given before performance of any study related procedure

• Adequate organ function, as specified below, within 21 days:

  • Bone marrow reserve consistent with: absolute neutrophil count (ANC) ≥ 1.5 x 109/L; platelet count ≥ 100 x 109/L; hemoglobin ≥ 9 g/dL;
  • Hepatic: total bilirubin ≤1.5 x upper limit of normal (ULN), transaminases (aspartate aminotransferase/serum glutamic oxaloacetic transaminase-AST/SGOT and alanine aminotransferase/serum glutamic pyruvic transaminase-ALT/SGPT) ≤2.5 x ULN (≤5 x ULN if liver metastases are present);
  • Renal: creatinine clearance ≥50 mL/min
  • Metabolic: fasting serum glucose (≤ 130 mg/dL) and fasting triglycerides ≤ 300 mg/dL
  • Left ventricular ejection fraction (LVEF) within 5 absolute percentage points of institutional standard of normal as measured by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) within 4 weeks prior to first study drug administration (ie, if the institutional normal is 50%, subject's LVEF may be as low as 45% to be eligible for the study)

• Female patients who:

  • Are postmenopausal for at least 1 year before the screening visit, OR
  • Are surgically sterile, OR
  • If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 90 days after the last dose of study drug, or agree to completely abstain from heterosexual intercourse

• Male patients, even if surgically sterilized (ie, status post-vasectomy), who:

  • Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, or
  • Agree to completely abstain from heterosexual intercourse

• Treatment with strong CYP2C19, CYP3A4, and CYP2C9 inhibitors and/or inducers must be discontinued

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Exclusion Criteria

• Female patients who are both lactating and breastfeeding or have a positive serum pregnancy test during the screening period

• Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment

• Treatment with any investigational products within 14 days

• Failed to recover from the reversible effects of prior anticancer therapies

• Manifestations of malabsorption due to prior gastrointestinal surgery or disease

• Poorly controlled diabetes mellitus

• History of any of the following within the last 6 months prior to study entry:

  • Ischemic myocardial event
  • Ischemic cerebrovascular event
  • Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia
  • Placement of a pacemaker for control of rhythm
  • New York Heart Association Class III or IV heart failure
  • Pulmonary embolism

• Significant active cardiovascular or pulmonary disease at the time of study entry, including:

  • Uncontrolled high blood pressure
  • Pulmonary hypertension
  • Uncontrolled asthma or O2 saturation < 90%
  • Significant valvular disease
  • Medically significant (symptomatic) bradycardia
  • History of arrhythmia requiring an implantable cardiac defibrillator
  • Baseline prolongation of the rate-corrected QT interval (QTc)

• Treatment with hematopoietic growth factors, transfusions of blood and blood products, or systemic corticosteroids

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Phase II: DTC Cohort	MLN0128	Phase II participants receive MLN0128 at the recommended phase II dose of 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent. All phase I participants treated at the maximum tolerated dose/ recommended phase II dose (DL3) are enrolled in the phase II part of the study according to the appropriate disease cohort.
Phase I: Dose Level 1 (PI DL1)	MLN0128	Phase I Dose Level 1 participants receive MLN0128 3 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent.
Phase I: Dose Level 2 (PI DL2)	MLN0128	Phase I Dose Level 3 (dose escalation) participants received MLN0128 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent.
Phase I: Dose Level 3 (PI DL3)	MLN0128	Phase I Dose Level 3 participants receive MLN0128 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent.
Phase II: ATC Cohort	MLN0128	Phase II participants receive MLN0128 at the recommended phase II dose of 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent. All phase I participants treated at the maximum tolerated dose/ recommended phase II dose (DL3) are enrolled in the phase II part of the study according to the appropriate disease cohort.
Phase I: Dose Level 3 (PI DL3) Expansion	MLN0128	Phase I Dose Level 3 participants receive MLN0128 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent.

Primary Outcome Measures

Name	Time	Method
Maximum Tolerated Dose (MTD) [Phase I Dose Escalation]	cycle 1 (cycle duration=28 days)	The MTD is determined by the number of participants who experience a dose limiting toxicity (DLT). The MTD is defined as the highest dose at which fewer than one-third of participants experience a DLT. If no DLTs are observed, the MTD is not reached but the highest dose received may be the Recommended Phase II Dose (RP2D).
Number of Participants With Dose Limiting Toxicity (DLT) [Phase I Dose Escalation]	cycle 1 (cycle duration=28 days)	DLT is defined as an adverse event based on the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) or abnormal laboratory value assessed as unrelated to disease, disease progression, intercurrent illness, or concomitant medications, that meets any of the criteria (hematologic, renal, hepatic, endocrine, metabolic/laboratory, pancreatitis, cardiac, neurotoxicity, mood alteration, dermatologic\] listed in section 5.3.2 of the protocol.
4-month Progression Free Survival (PFS4) Rate - ATC Cohort [Phase II]	Disease was assessed radiologically every 2 cycles/ 8 weeks on treatment until the earliest of first progression, death or 24 months from study entry. Relevant for this endpoint was observation at 4-months.	PFS4 rate is the percentage of participants remaining alive and progression-free at 4-months from study entry. Per RECIST 1.1 for target lesions: disease progression (PD) is at least a 20% increase in sum longest diameter (LD), taking as reference the smallest sum on study with at least 5 mm absolute increase or the appearance of one or more new lesions. For non-target lesions, PD is appearance of one or more new lesions or unequivocal progression of existing non-target lesions.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Grade 3-5 Treatment-related Toxicity [Phase I/Phase II]	Assessed on treatment at cycles 1 and 2 (days 1 and 15), cycle 3+ on day 1, at the end of treatment and up to 30 days post-treatment. Participants were on treatment up to 21.6 months (median 2.1 months).	All grade 3-5 adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAEv4 as reported on case report forms were counted. Maximum grade toxicity by AE type was then calculated. Incidence is the number of participants experiencing at least one grade 2-5 treatment-related AE during the time of observation.
6-month Progression Free Survival (PFS6) Rate - DTC Cohort [Phase II]	Disease was assessed radiologically every 2 cycles/ 8 weeks on treatment until the earliest of first progression, death or 24 months from study entry. Relevant for this endpoint was observation at 6-months.	PFS6 rate is the percentage of patients remaining alive and progression-free at 6-months from study entry. Per RECIST 1.1 for target lesions: disease progression (PD) is at least a 20% increase in sum longest diameter (LD), taking as reference the smallest sum on study with at least 5 mm absolute increase or the appearance of one or more new lesions. For non-target lesions, PD is appearance of one or more new lesions or unequivocal progression of existing non-target lesions.
Overall Response Rate (ORR) [Phase II]	Disease was assessed radiologically every 2 cycles/ 8 weeks on treatment until the earliest of first progression, death or 24 months from study entry. Participants were on treatment up to 196 days (PII ATC) and 454 days (PII DTC).	ORR was defined as the percentage of participants achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions; PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. Confirmatory scan obtained 8 weeks following initial documentation of objective response.
Median Overall Survival (OS) [Phase II]	Long term follow-up for survival was every 3 months post-treatment end up to 24 months.	OS based on the Kaplan-Meier method is defined as the time from study entry to death or censored at date last known alive.
BRAF V600E Status [Phase II]	Baseline	Participants were classified by BRAF V600E mutation status evaluated by next generation sequencing (NGS) platforms using tumor tissue collected at baseline.
Clinical Benefit (CBR) by BRAF V600E Status [Phase II]	BRAF V600E status per NGS at baseline. Disease response was assessed every 2 cycles on treatment until the first progression, death or 24 months from study entry. Participants were on treatment up to 196 days (PII ATC) and 454 days (PII DTC).	CBR was defined as the percentage of participants achieving complete response (CR), partial response (PR) or stable disease (SD) based on RECIST 1.1 criteria. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions; PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. Confirmatory scan obtained 8 weeks following initial documentation of CR or PR. SD is neither PR or better nor PD (defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum since treatment start, or the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions). Participants were classified by BRAF V600E status based on established methods using tumor tissue collected at baseline.

Trial Locations

Locations (3)

Hoag Memorial Hospital Presbyterian; 🇺🇸 Newport Beach, California, United States

Dana-Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

University of Michigan Medical School; 🇺🇸 Ann Arbor, Michigan, United States