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.

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.

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

Individual participant data (IPD) will not be shared. Cumulative data will be posted here and published.

The analysis population is comprised of all enrolled participants.

Assessed on treatment and for this study cohort the longest treatment duration was approximately 4 months in each dose level 1 and 2.

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.

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