Patient case: 54-year-old male with Gastric cancer. Genetic variant: PIK3CA (E545K). Other conditions: Depression.

Clinical trial: Phase 1 Study of ARQ 751 in Solid Tumors With AKT1, 2, 3 Genetic Alterations, Activating PI3K Mutations or PTEN-null

Summary: An open-label, Phase 1, dose escalation study of ARQ 751 in subjects with advanced solid tumors with AKT1, 2, 3 genetic alterations, activating PI3K mutations or PTEN-null.

Detailed description: This is an open-label, Phase 1, dose escalation study of ARQ 751 administered orally to subjects with advanced solid tumors with AKT1, 2, 3 genetic alterations, activating PI3K mutations or PTEN-null.

Eligibility: Inclusion Criteria:
  1. Signed written informed consent granted prior to initiation of any study-specific procedures
  2. 18 years of age and older
  3. Histologically or cytologically documented locally advanced, inoperable or metastatic solid tumors with documented AKT1, 2, 3 genetic alterations, activating PI3K mutations or PTEN null
  4. Failure to respond to standard therapy, or for whom standard or curative therapy does not exist, or is not tolerable.
  a. Subjects enrolled in the Expanded Cohort should have no more than 3 prior systemic regimens with confirmed disease progression. If the subject is refractory or has disease progression within 6 months of the adjuvant treatment, then the previous treatment should be considered as the line of treatment rather than an adjuvant therapy.
  5. Measurable disease
  6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2
  7. Archival tissue samples and/or fresh tumor biopsy samples:
  1. Subjects should agree to provide archival and/or fresh tumor biopsy samples
  2. Archival tumor samples should be collected for all enrolled subjects; if archival tissue samples are not available, a recent core needle biopsy should be collected
  3. Paired, pre- and post-treatment, tumor biopsy is optional for subjects enrolled in the Dose Escalation and Food-effect cohorts
  4. Paired tumor biopsy is mandatory for all subjects enrolled in the Expanded cohort; subjects should agree to and be eligible for paired tumor biopsy
  8. Adequate organ function as indicated by the following laboratory values. All laboratory tests must be obtained within 7 days prior to the first dose of ARQ 751:
  a. Hematological i. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L ii. Platelet count (Plt) ≥ 100 x 109/L iii. Hemoglobin (Hb) ≥ 9 g/dL iv. International normalized ratio (INR) 0.8 to upper limit of normal (ULN) or ≤ 3 for subjects receiving anticoagulant therapy such as Coumadin or heparin b. Renal i. Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 60 mL/min/1.73 m2 for subjects with serum creatinine levels > 1.5 x institutional ULN c. Hepatic i. Total bilirubin ≤ 1.5 x ULN ii. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN or ≤ 5 x ULN for subjects with known liver metastases d. Metabolic i. Glycated hemoglobin (HbA1c) ≤ 8%
  9. If a subject is currently receiving bisphosphonates, the subject must have received the bisphosphonates for at least four weeks prior to the first dose of ARQ 751.
  a. Initiation of bisphosphonates during the study may be allowed provided the subject completes the first cycle of treatment without any dose limiting toxicity (DLT) and the Investigator rules out tumor progression.
  10. Male or female subjects of child-producing potential must agree to use double-barrier contraceptive measures, oral contraception, or avoidance of intercourse during the study and for 90 days after the last dose of ARQ 751.
  11. Women of childbearing potential must have a negative serum pregnancy test during the Screening Period and within 48 hours of the first dose of ARQ 751. "Women of childbearing potential" is defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months prior to the first dose of ARQ 751.
  Exclusion Criteria:
  1. Anti-cancer therapy, such as chemotherapy, immunotherapy, targeted, and hormonal/endocrine therapy, or investigational agents within four weeks prior to administration of the first dose of study drug (two weeks for orally administered drugs and six weeks for nitrosoureas, mitomycin C, or bevacizumab)
  1. To be eligible for study treatment, toxicity from prior treatment must recover to Grade ≤ 1, except for alopecia
  2. Concurrent systemic high-dose corticosteroids when used intermittently in an antiemetic regimen, for central nervous system (CNS) metastases management, or as a part of the premedication regimen are allowed
  3. Concurrent standard long-term anticancer hormonal therapy with drugs including, but not limited to, selective estrogen receptor modulators or Gonadotropin-releasing hormone (GnRH) analogs if started at least six months before the first dose of ARQ 751 is allowed
  2. Radiation therapy within four weeks prior to administration of the first dose of ARQ 751
  1. To be eligible for study treatment, radiation therapy-related toxicity must recover to Grade ≤ 1 prior to administration of the first dose of ARQ 751.
  2. Concurrent palliative radiotherapy for local pain-control may be allowed provided the subject completes the first cycle of treatment, does not meet criteria of progressive disease, and treated lesions will not be included in the target/non-target lesion assessment.
  3. Major surgical procedure within four weeks prior to administration of the first dose of ARQ 751
  a. To be eligible for the study treatment, all surgical wounds must be fully healed and any surgery-related adverse events must recover to Grade ≤ 1.
  4. Previous treatment with AKT inhibitors (e.g., ARQ 092, MK-2206, GSK2141795, AZD5363)
  5. Unable or unwilling to swallow the complete daily dose of ARQ 751
  6. A corrected QT interval (QTc) ≥ 480 msec using the Fridericia's formula (QTcF)
  7. History of Type 1 or 2 diabetes mellitus requiring regular medication (other than oral hypoglycemic agents) or fasting glucose ≥ 160 mg/dL at the Pre-Study visit
  8. Significant gastrointestinal (GI) disorder(s) that could, in the opinion of the Investigator, interfere with the absorption, metabolism, or excretion of ARQ 751 (e.g., Crohn's disease, ulcerative colitis, extensive gastric resection)
  9. Known active CNS metastases and/or carcinomatous meningitis
  a. To be eligible for the study treatment, subjects must have stable disease ≥ 1 month, confirmed by magnetic resonance imaging (MRI) or computed tomography (CT) scan, and have CNS metastases well controlled by low-dose steroids, anti-epileptics, or other symptom-relieving medications.
  10. History of myocardial infarction (MI) or New York Heart Association (NYHA) Class II-IV congestive heart failure within 6 months of the administration of the first dose of ARQ 751 (MI occurring > 6 months of the first dose of ARQ 751 will be permitted); Grade 2 or worse conduction defect (e.g., right or left bundle branch block)
  11. Concurrent severe uncontrolled illness not related to cancer and social situation that would limit compliance with study requirements, including but not limited to:
  1. Psychiatric illness, substance abuse
  2. Ongoing or active known infection, including human immunodeficiency virus (HIV) infection
  12. Active or history of other malignancy other than the current cancer within 2 years of the first dose of ARQ 751, with the exception of carcinoma in-situ of the cervix, basal cell carcinoma, and superficial bladder tumors curatively treated
  13. Blood transfusion or administration of growth factors within 5 days prior to a blood draw being used to confirm eligibility
  14. Pregnant or breastfeeding

Relevance to patient case: possibly relevant