Patient case: 68-year-old male with melanoma; genetic feature: PTEN loss of function

Clinical trial: First-in-Human Dose Escalation Trial in Subjects With Advanced Malignancies

Summary: This is a Phase 1, first-in-human, open-label, non-randomized, dose escalation, trial to explore the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD) and clinical activity signals of MSC2363318A.


Eligibility: Inclusion Criteria:
  -  Age greater than or equal to (>=)18 years
  -  Confirmed diagnosis of advanced malignancies that may be controlled with p70S6K or Akt inhibition based on already identified molecular alteration known to affect the PAM pathway, such as:: such as: such as: phosphate and tensin homolog (PTEN), phosphoinositide 3-Kinase catalytic subunit alpha isoform (PI3KCA), protein kinase B 1 (Akt 1), Akt 3, mammalian target of rapamycin (mTOR), tumor sclerosis complex 1 (TSC1), tumor sclerosis complex 2 (TSC2), in subjects who have received at least all treatment options considered to be standard therapy, unless some available treatment are not acceptable to the subject. For the dose escalation portion of the trial, subjects must have received the standard therapy unless intolerant or contraindicated.
  -  Part 2, Cohort 1: For subjects with PAM pathway alterations, subjects must have only PAM alterations, excluding Akt2 activating mutations or amplifications, and no other confounding genomic alterations.
  -  Part 2, Cohort 2: Histologically confirmed local laboratory testing (immunohistochemistry 3+ staining and/or fluorescence in situ hybridization ratio ≥ 2.0) HER2+ metastatic breast cancer subjects who are resistant to trastuzumab-containing treatment and progressed on trastuzumab, pertuzumab, a taxane, and/or trastuzumab emtansine. There is no limit regarding the number of prior lines of therapy.
  -  Part 2, Cohort 3: Histologically and/or cytologically confirmed diagnosis of breast cancer with hormone receptor-positive status (ER and/or PgR positive) and HER2-negative status with prior exposure to tamoxifen and/or an aromatase inhibitor and/or an aromatase inhibitor plus palbociclib. Prior treatment with tamoxifen in the neoadjuvant setting is allowed but must have been discontinued for at least 1 year prior to the first dose.
  -  Measurable disease using clinically appropriate criteria for the type of malignancy, RECIST version 1.1 for solid tumors and Cheson 2007 for lymphoma
  -  A tumor accessible for biopsies and consent to undergo tumor biopsies before and during MSC2363318A treatment
  -  Ability to read and understand the informed consent form and willingness and ability to give informed consent and demonstrate comprehension of the trial before undergoing any trial activities
  -  Negative blood pregnancy test at the screening visit for women of childbearing potential
  -  Willingness to avoid pregnancy and breast feeding beginning two weeks before the first MSC2363318A dose and ending three months after the last trial treatment. Male subjects with female partners of childbearing potential and female subjects of childbearing potential must use adequate contraception in the judgment of the Investigator, such as a two barrier method or a one barrier method with spermicide or intrauterine device
  Exclusion Criteria:
  -  Eastern Cooperative Oncology Group Performance Status >=2
  -  Previous therapy with:
  -  Previous treatment of the currently malignancy with a PAM Pathway Inhibitor
  -  Chemotherapy, immunotherapy, hormonal therapy (except low dose corticosteroids), biologic therapy, or any other anticancer therapy within 1 month (or five elimination half-lives for noncytotoxics, whichever is shorter) of Day 1 of trial drug treatment (6 weeks for nitrosureas or mitomycin
  -  Any investigational agent within 28 days of Day 1 of trial drug treatment
  -  Extensive prior radiotherapy on more than 30 percent of bone marrow reserves, or prior bone marrow/stem cell transplantation within 5 years from enrolment
  -  Known tumor EGFR, KRAS, and/or Akt2 mutations of amplification
  -  Ongoing toxicity (except alopecia) due to a prior therapy, unless returned to baseline or Grade 1 or less
  -  Major surgical intervention or participation in a therapeutic clinical trial within 28 days from Day 1 of the first dose of MSC2363318A
  -  Bone marrow impairment, renal impairment, liver function abnormality and impaired cardiac function as defined in the protocol
  -  History of cerebral vascular accident or stroke within the previous 2 years
  -  Uncontrolled hypertension
  -  History of Grade 3 or 4 allergic reactions attributed to compounds of similar chemical or biologic composition as MSC2363318A
  -  Known active central nervous system (CNS) metastases
  -  History of difficulty swallowing, malabsorption or other chronic gastrointestinal disease or conditions that may hamper compliance and/or absorption of the investigational product
  -  Known human immunodeficiency virus, viral hepatitis, or tuberculosis positivity
  -  Legal incapacity or limited legal capacity
  -  Any other condition which, in the opinion of the Investigator, might impair the subject's tolerance of trial treatment, the safety of the individual subject or the outcome of the trial

Relevance to patient case: not relevant