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

NCT02244463 | Completed Phase 1 Results DMC

• 1 other identifier: 14-223
• Study Type: interventional
• Target: 46
• Locations: 1 country
• Sites: 3

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.

Conditions

Anaplastic Thyroid Cancer; Thyroid Cancer; Differentiated Thyroid Cancer

Keywords

Anaplastic Thyroid Cancer; Thyroid Cancer; Differentiated Thyroid Cancer

Outcome Measures

Primary Outcomes (3)

• Maximum Tolerated Dose (MTD) [Phase I Dose Escalation]

  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).

  cycle 1 (cycle duration=28 days)

• Number of Participants With Dose Limiting Toxicity (DLT) [Phase I Dose Escalation]

  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.

  cycle 1 (cycle duration=28 days)

• 4-month Progression Free Survival (PFS4) Rate - ATC Cohort [Phase II]

  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.

  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.

Secondary Outcomes (6)

• 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).

• 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.

• 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).

• Median Overall Survival (OS) [Phase II]

  Long term follow-up for survival was every 3 months post-treatment end up to 24 months.

• BRAF V600E Status [Phase II]

  Baseline

Study Arms (6)

Phase I: Dose Level 1 (PI DL1)

EXPERIMENTAL

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.

Drug: MLN0128

Phase I: Dose Level 2 (PI DL2)

EXPERIMENTAL

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.

Drug: MLN0128

Phase I: Dose Level 3 (PI DL3)

EXPERIMENTAL

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.

Drug: MLN0128

Phase I: Dose Level 3 (PI DL3) Expansion

EXPERIMENTAL

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.

Drug: MLN0128

Phase II: ATC Cohort

EXPERIMENTAL

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.

Drug: MLN0128

Phase II: DTC Cohort

EXPERIMENTAL

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.

Drug: MLN0128

Interventions

MLN0128 DRUG

Also known as: INK128, Sapanisertib

Phase I: Dose Level 1 (PI DL1); Phase I: Dose Level 2 (PI DL2); Phase I: Dose Level 3 (PI DL3); Phase I: Dose Level 3 (PI DL3) Expansion; Phase II: ATC Cohort; Phase II: DTC Cohort

Eligibility Criteria

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

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Dana-Farber Cancer Institute: lead
• Millennium Pharmaceuticals, Inc.: collaborator

Study Sites (3)

Hoag Memorial Hospital Presbyterian

Newport Beach, California, 92663, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

University of Michigan Medical School

Ann Arbor, Michigan, 48109, United States

Location

Related Publications (1)

• Cabanillas ME, McFadden DG, Durante C. Thyroid cancer. Lancet. 2016 Dec 3;388(10061):2783-2795. doi: 10.1016/S0140-6736(16)30172-6. Epub 2016 May 27.

  PMID: 27240885 DERIVED

MeSH Terms

Conditions

Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms

Interventions

sapanisertib

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Endocrine Gland Neoplasms; Neoplasms by Site; Head and Neck Neoplasms; Endocrine System Diseases; Thyroid Diseases

Results Point of Contact

• Title: Kartik Sehgal, MD
• Organization: Dana-Farber Cancer Institute

Kartik_Sehgal@dfci.harvard.edu

(617) 632-3090

Study Officials

• Kartik Seghal, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: September 17, 2014
• First Posted: September 19, 2014
• Study Start: July 1, 2015
• Primary Completion: April 28, 2022
• Study Completion: April 28, 2022
• Last Updated: January 12, 2024
• Results First Posted: January 12, 2024

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)