MLN0128 in Recurrent/Metastatic Merkel Cell Carcinoma

• Sponsor: Dana-Farber Cancer Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT02514824
• Collaborator: Millennium Pharmaceuticals, Inc. (Industry)
• Enrollment: 9
• Location: 1
• Arms: 4
• Actual Duration (Months): 20
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This research study is studying a targeted therapy as a possible treatment for merkel cell carcinoma.

• The name of the study intervention involved in this study is: MLN0128.

Condition or Disease	Intervention/Treatment	Phase
Merkel Cell Carcinoma	Drug: MLN0128	Phase 1/Phase 2

Detailed Description

This is a phase I/II clinical trial. A phase I clinical trial tests the safety of an investigational intervention and also tries to define the appropriate dose of the investigational intervention to use for further studies. "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 may prevent tumor cells from dividing and growing by selectively and potently inhibiting a chemical, mTOR kinase, which regulates cell growth and survival.

Patients with merkel cell carcinoma have been observed to sometimes carry genetic alterations in their tumor cells which may make the cancer more sensitive to inhibition by MLN0128. In this research study,the investigators are studying the usefulness of MLN0128 in merkel cell carcinoma cases.

Study Design

• Study Type: Interventional
• Actual Enrollment: 9 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: MLN0128 in Recurrent/Metastatic Merkel Cell Carcinoma
• Actual Study Start Date: Oct 1, 2015
• Actual Primary Completion Date: Apr 1, 2017
• Actual Study Completion Date: Jun 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dose Level 1: MLN01283 3 mg (Phase 1) Phase 1 dose level 1 participants receive MLN01283 3 mg orally once daily of a 28 day cycle. Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.	Drug: MLN0128; Investigational mTOR kinase inhibitor; Other Names: INK128
Experimental: Dose Level 2: MLN01283 4 mg (Phase 1) Phase 1 dose level 2 participants receive MLN01283 4 mg orally once daily of a 28 day cycle. Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.	Drug: MLN0128; Investigational mTOR kinase inhibitor; Other Names: INK128
Experimental: Dose Level 3: MLN01283 5 mg (Phase 1) Phase 1 dose level 3 participants receive MLN01283 5 mg orally once daily of a 28 day cycle. Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.	Drug: MLN0128; Investigational mTOR kinase inhibitor; Other Names: INK128
Experimental: MLN01283 RP2D (Phase 2) Phase 2 participants receive MLN01283 at the recommended phase 2 dose (RP2D) orally once daily of a 28 day cycle. Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.	Drug: MLN0128; Investigational mTOR kinase inhibitor; Other Names: INK128

Outcome Measures

Primary Outcome Measures

1. MLN01283 Maximum Tolerated Dose (MTD) [Phase I] [The observation period for DLT evaluation was the first 28 days (cycle 1) of treatment.]

   The MLN01283 MTD is determined by the number of participants who experience a dose limiting toxicity (DLT). See subsequent primary outcome measure for the DLT definition. The MTD is defined as the highest dose at which fewer than one-third of patients 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).

2. Dose Limiting Toxicity (DLT) [Phase I] [The observation period for DLT evaluation was the first 28 days (cycle 1) of treatment.]

   A DLT was defined as an adverse event (AE) assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications meets any of the following criteria including but not limited to: grade (G) 4-5 AEs, G3 thrombocytopenia, neutropenia, AST, ALT, serum creatinine or total bilirubin 2 to 3 x upper limit normal (ULN), aymptomatic amylase and/or lipase lasting >7 consecutive days; febrile neutropenia; G3 cardiac, hyperglycemia, mood alteration; G2 pancreatitis; G2 hyperglycemia unresolved within 14 days; G2 mood alteration unresolved in 14 days despite medical treatment; Dose interruption >21 days due to G2 dematologic; one grade level increase neurotoxicity.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Metastatic or recurrent MCC confirmed by histology

• Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as > 20 mm with conventional techniques or as > 10 mm with spiral CT scan (see section 10 for the evaluation of measureable disease). Tumors within a previously irradiated field will be designated as "non-target" lesions unless progression is documented

• Age 18 years or older

• ECOG performance status ≤ 2

• Participants must have normal organ and marrow function

• 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

• 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

• Tissue for correlative studies must be available (paraffinized or frozen)

• Ability to swallow oral medications and maintain an empty stomach state for 2 hours prior to the MLN0128 dose and for 1 hour following administration

• Ability to understand and the willingness to sign a written informed consent

Exclusion Criteria:

• Participants who have had chemotherapy or radiotherapy within 2 weeks prior to entering the study

• The subject has active brain metastases or epidural disease

• Participants who are receiving any other investigational agents within 14 days before the first dose of study drug

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations

• Female patients who are both lactating and breastfeeding or have a positive serum pregnancy test during the screening period or a positive urine pregnancy test on Day 1 before first dose of study drug

• Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an unknown reason that may alter the absorption of MLN0128

• 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 (NYHA) 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

• Significant valvular disease; severe regurgitation or stenosis

• Medically significant (symptomatic) bradycardia

• History of arrhythmia requiring an implantable cardiac defibrillator

• Baseline prolongation of the rate-corrected QT interval (QTc)

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215

Sponsors and Collaborators

• Dana-Farber Cancer Institute
• Millennium Pharmaceuticals, Inc.

Investigators

• Principal Investigator: Robert Haddad, MD, Dana-Farber Cancer Institute

Study Documents (Full-Text)

• Study Protocol - Mar 18, 2016

More Information

Publications

None provided.

• Responsible Party: Robert I. Haddad, MD, Principal Investigator, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT02514824
• Other Study ID Numbers: 15-223
• First Posted: Aug 4, 2015
• Last Update Posted: Dec 29, 2020
• Last Verified: Dec 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Robert I. Haddad, MD, Principal Investigator, Dana-Farber Cancer Institute: recurrent merkel cell carcinoma; metastatic merkel cell carcinoma
• Additional relevant MeSH terms: Carcinoma, Merkel Cell; Carcinoma

Study Results

Participant Flow

Recruitment Details	Participants enrolled from October 2015 through March 2017.

Arm/Group Title	Dose Level 1: MLN01283 3 mg (Phase 1)	Dose Level 2: MLN01283 4 mg (Phase 1)	Dose Level 3: MLN01283 5 mg (Phase 1)	MLN01283 RP2D (Phase 2)
Arm/Group Description	Phase 1 dose level 1 participants receive MLN01283 3mg orally once daily of a 28 day cycle. Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.	Phase 1 dose level 2 participants receive MLN01283 4 mg orally once daily of a 28 day cycle. Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.	Phase 1 dose level 3 participants receive MLN01283 5 mg orally once daily of a 28 day cycle. Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.	Phase 2 participants receive MLN01283 at the recommended phase 2 dose (RP2D) orally once daily of a 28 day cycle. Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.
Period Title: Overall Study
STARTED	4	5	0	0
Evaluable for Dose-limiting Toxicity	3	5	0	0
COMPLETED	3	4	0	0
NOT COMPLETED	1	1	0	0

Baseline Characteristics

Arm/Group Title	Dose Level 1: MLN01283 3 mg (Phase 1)	Dose Level 2: MLN01283 4 mg (Phase 1)	Total
Arm/Group Description	Phase 1 dose level 1 participants receive MLN01283 3mg orally once daily of a 28 day cycle. Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.	Phase 1 dose level 2 participants receive MLN01283 4 mg orally once daily of a 28 day cycle. Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.	Total of all reporting groups
Overall Participants	4	5	9
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	69	69	69
Sex: Female, Male (Count of Participants)
Female	4 100%	5 100%	9 100%
Male	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	4 100%	5 100%	9 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	4 100%	5 100%	9 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	4 100%	5 100%	9 100%

Outcome Measures

1. Primary Outcome

Title	MLN01283 Maximum Tolerated Dose (MTD) [Phase I]
Description	The MLN01283 MTD is determined by the number of participants who experience a dose limiting toxicity (DLT). See subsequent primary outcome measure for the DLT definition. The MTD is defined as the highest dose at which fewer than one-third of patients 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).
Time Frame	The observation period for DLT evaluation was the first 28 days (cycle 1) of treatment.

Outcome Measure Data

Analysis Population Description

All P1 participants who received at least one dose of the study drug were evaluable for the DLT analysis. Participants who discontinued study treatment prior to end of cycle 1 for reason other than dose-limiting toxicity were replaced.

Arm/Group Title	All Phase 1 Participants
Arm/Group Description	Phase 1 participants received MLN01283 according to the established dose escalation schedule. Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.
Measure Participants	8
Number [mg]	3

2. Primary Outcome

Title	Dose Limiting Toxicity (DLT) [Phase I]
Description	A DLT was defined as an adverse event (AE) assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications meets any of the following criteria including but not limited to: grade (G) 4-5 AEs, G3 thrombocytopenia, neutropenia, AST, ALT, serum creatinine or total bilirubin 2 to 3 x upper limit normal (ULN), aymptomatic amylase and/or lipase lasting >7 consecutive days; febrile neutropenia; G3 cardiac, hyperglycemia, mood alteration; G2 pancreatitis; G2 hyperglycemia unresolved within 14 days; G2 mood alteration unresolved in 14 days despite medical treatment; Dose interruption >21 days due to G2 dematologic; one grade level increase neurotoxicity.
Time Frame	The observation period for DLT evaluation was the first 28 days (cycle 1) of treatment.

Outcome Measure Data

Analysis Population Description

All P1 participants who received at least one dose of the study drug were evaluable for the DLT analysis. Participants who discontinued study treatment prior to end of cycle 1 for reason other than dose-limiting toxicity were replaced.

Arm/Group Title	Dose Level 1: MLN01283 3 mg (Phase 1)	Dose Level 2: MLN01283 4 mg (Phase 1)
Arm/Group Description	Phase 1 dose level 1 participants receive MLN01283 3mg orally once daily of a 28 day cycle. Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.	Phase 1 dose level 2 participants receive MLN01283 4 mg orally once daily of a 28 day cycle. Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.
Measure Participants	3	5
Count of Participants [Participants]	0 0%	2 40%

3. Post-Hoc Outcome

Title	Number of Participants With Objective Response (OR) [Phase 1]
Description	Objective response is defined as achieving complete response (CR) or partial response (PR) on treatment based on RECIST 1.1 criteria. For target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD.
Time Frame	Assessed on treatment and for this study cohort the longest treatment duration was approximately 4 months in each dose level 1 and 2.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dose Level 1: MLN01283 3 mg (Phase 1)	Dose Level 2: MLN01283 4 mg (Phase 1)
Arm/Group Description	Phase 1 dose level 1 participants receive MLN01283 3mg orally once daily of a 28 day cycle. Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.	Phase 1 dose level 2 participants receive MLN01283 4 mg orally once daily of a 28 day cycle. Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.
Measure Participants	4	5
Count of Participants [Participants]	0 0%	0 0%

Adverse Events

Time Frame	Assessed on treatment and for this study cohort the longest treatment duration was approximately 4 months in each dose level 1 and 2.
Adverse Event Reporting Description	Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Arm/Group Title	Dose Level 1: MLN01283 3 mg (Phase 1)		Dose Level 2: MLN01283 4 mg (Phase 1)
Arm/Group Description	Phase 1 dose level 1 participants receive MLN01283 3mg orally once daily of a 28 day cycle. Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.		Phase 1 dose level 2 participants receive MLN01283 4 mg orally once daily of a 28 day cycle. Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.
All Cause Mortality
	Dose Level 1: MLN01283 3 mg (Phase 1)		Dose Level 2: MLN01283 4 mg (Phase 1)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/4 (75%)		3/5 (60%)
Serious Adverse Events
	Dose Level 1: MLN01283 3 mg (Phase 1)		Dose Level 2: MLN01283 4 mg (Phase 1)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		3/5 (60%)
Blood and lymphatic system disorders
Anemia	0/4 (0%)		1/5 (20%)
Gastrointestinal disorders
Nausea	0/4 (0%)		1/5 (20%)
Gastrointestinal disorders - Other	0/4 (0%)		1/5 (20%)
Metabolism and nutrition disorders
Hyperglycemia	0/4 (0%)		1/5 (20%)
Other (Not Including Serious) Adverse Events
	Dose Level 1: MLN01283 3 mg (Phase 1)		Dose Level 2: MLN01283 4 mg (Phase 1)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/4 (100%)		5/5 (100%)
Cardiac disorders
Pericardial effusion	0/4 (0%)		1/5 (20%)
Sinus tachycardia	0/4 (0%)		1/5 (20%)
Endocrine disorders
Hyperthyroidism	0/4 (0%)		1/5 (20%)
Gastrointestinal disorders
Abdominal pain	1/4 (25%)		0/5 (0%)
Constipation	0/4 (0%)		2/5 (40%)
Diarrhea	1/4 (25%)		2/5 (40%)
Dry mouth	0/4 (0%)		1/5 (20%)
Gastroesophageal reflux disease	0/4 (0%)		1/5 (20%)
Gastrointestinal disorders - Other	1/4 (25%)		1/5 (20%)
Nausea	2/4 (50%)		4/5 (80%)
Vomiting	0/4 (0%)		2/5 (40%)
General disorders
Fall	0/4 (0%)		1/5 (20%)
Fatigue	3/4 (75%)		2/5 (40%)
Pain	1/4 (25%)		0/5 (0%)
Infections and infestations
Infections and infestations - Other	1/4 (25%)		0/5 (0%)
Sinusitis	0/4 (0%)		1/5 (20%)
Skin infection	1/4 (25%)		0/5 (0%)
Upper respiratory infection	1/4 (25%)		0/5 (0%)
Urinary tract infection	1/4 (25%)		0/5 (0%)
Urinary urgency	1/4 (25%)		0/5 (0%)
Investigations
CPK increased	0/4 (0%)		1/5 (20%)
Creatinine increased	0/4 (0%)		1/5 (20%)
Weight loss	1/4 (25%)		3/5 (60%)
Metabolism and nutrition disorders
Anorexia	1/4 (25%)		2/5 (40%)
Dehydration	1/4 (25%)		1/5 (20%)
Hyperglycemia	2/4 (50%)		3/5 (60%)
Hyperkalemia	1/4 (25%)		0/5 (0%)
Hypokalemia	1/4 (25%)		2/5 (40%)
Hyponatremia	1/4 (25%)		2/5 (40%)
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	0/4 (0%)		2/5 (40%)
Pain in extremity	0/4 (0%)		1/5 (20%)
Nervous system disorders
Dizziness	0/4 (0%)		2/5 (40%)
Dysgeusia	0/4 (0%)		1/5 (20%)
Headache	0/4 (0%)		1/5 (20%)
Paresthesia	0/4 (0%)		1/5 (20%)
Presyncope	0/4 (0%)		1/5 (20%)
Syncope	0/4 (0%)		1/5 (20%)
Tremor	0/4 (0%)		1/5 (20%)
Psychiatric disorders
Agitation	0/4 (0%)		1/5 (20%)
Confusion	0/4 (0%)		1/5 (20%)
Insomnia	1/4 (25%)		0/5 (0%)
Renal and urinary disorders
Bladder spasm	0/4 (0%)		1/5 (20%)
Hematuria	0/4 (0%)		1/5 (20%)
Urinary retention	0/4 (0%)		1/5 (20%)
Respiratory, thoracic and mediastinal disorders
Cough	1/4 (25%)		3/5 (60%)
Dyspnea	0/4 (0%)		1/5 (20%)
Skin and subcutaneous tissue disorders
Pain of skin	1/4 (25%)		0/5 (0%)
Pruritus	2/4 (50%)		1/5 (20%)
Rash acneiform	1/4 (25%)		0/5 (0%)
Vascular disorders
Hypotension	0/4 (0%)		2/5 (40%)

Limitations/Caveats

The study did not proceed to phase 2 due to slow accrual and lack of efficacy.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.