Merkel Cell Carcinoma
Conditions
Keywords
recurrent merkel cell carcinoma, metastatic merkel cell carcinoma
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.
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.
Interventions
DRUGMLN0128
Investigational mTOR kinase inhibitor
Sponsors
Millennium Pharmaceuticals, Inc.
Dana-Farber Cancer Institute
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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). |
| 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. |
Countries
United States
Participant flow
Recruitment details
Participants enrolled from October 2015 through March 2017.
Participants by arm
| Arm | Count |
|---|---|
| Dose Level 1: MLN01283 3 mg (Phase 1) 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. | 4 |
| 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. | 5 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Dose-Limiting Toxicity | 0 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Dose Level 1: MLN01283 3 mg (Phase 1) | Total | Dose Level 2: MLN01283 4 mg (Phase 1) |
|---|---|---|---|
| Age, Continuous | 69 years | 69 years | 69 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 9 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 9 Participants | 5 Participants |
| Region of Enrollment United States | 4 participants | 9 participants | 5 participants |
| Sex: Female, Male Female | 4 Participants | 9 Participants | 5 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 4 | 3 / 5 |
| other Total, other adverse events | 4 / 4 | 5 / 5 |
| serious Total, serious adverse events | 0 / 4 | 3 / 5 |
Outcome results
Primary
Dose Limiting Toxicity (DLT) [Phase I]
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.
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Phase 1 Participants | Dose Limiting Toxicity (DLT) [Phase I] | 0 Participants |
| Dose Level 2: MLN01283 4 mg (Phase 1) | Dose Limiting Toxicity (DLT) [Phase I] | 2 Participants |
Primary
MLN01283 Maximum Tolerated Dose (MTD) [Phase I]
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.
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| All Phase 1 Participants | MLN01283 Maximum Tolerated Dose (MTD) [Phase I] | 3 mg |
Post Hoc
Number of Participants With Objective Response (OR) [Phase 1]
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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Phase 1 Participants | Number of Participants With Objective Response (OR) [Phase 1] | 0 Participants |
| Dose Level 2: MLN01283 4 mg (Phase 1) | Number of Participants With Objective Response (OR) [Phase 1] | 0 Participants |