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

Clinical trial: Open-label Phase 1b Study of ARQ 092 in Combination With Carboplatin Plus Paclitaxel, in Combination With Paclitaxel, or in Combination With Anastrozole

Summary: An Open-label Phase 1b Study of ARQ 092 in Combination with Carboplatin Plus Paclitaxel, in Combination with Paclitaxel, or in Combination with Anastrozole in Subjects with Selected Solid Tumors

Detailed description: This is an open-label Phase 1b, dose escalation study of oral ARQ 092 administered in combination with carboplatin plus paclitaxel (Carboplatin Plus Paclitaxel Arm) or in combination with paclitaxel alone (Paclitaxel Arm) in subjects with advanced, inoperable metastatic and/or recurrent solid tumors, or in combination with anastrozole (Anastrozole Arm) in subjects with ovarian or endometrial cancer.

Eligibility: Inclusion Criteria:
  1. Signed written informed consent form
  2. 18 years of age or older
  3. Histologically or cytologically confirmed locally advanced, inoperable, or metastatic tumors:
  • Carboplatin Plus Paclitaxel Arm:
  -  Subjects with any tumor type (except lung) for which carboplatin plus paclitaxel chemotherapy would be appropriate
  • Paclitaxel Arm:
  -  Subjects with any tumor type (except lung) for which paclitaxel chemotherapy would be appropriate
  • Anastrozole Arm:
  -  Subjects with ovarian and endometrial cancer with:
  -  Documented/locally determined AKT1 or PIK3CA mutation
  -  ER+ status
  4. Female subjects of child-bearing potential must have a negative serum or urine pregnancy test within 72 hours prior to administration of the first dose of study drug. "Women of childbearing potential" is defined as sexually mature women who have not undergone hysterectomy and/or bilateral oophorectomy, or who have not been naturally postmenopausal for at least 12 consecutive months prior to administration of the first dose of the study drug.
  5. Measurable or evaluable disease
  6. Subjects must agree to provide archival and/or fresh tissue biopsy samples, if available. Tumor biopsy will be done only if the subject has a lesion for which, in the opinion of the Investigator, a non- or minimally invasive tumor biopsy may be performed.
  7. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
  8. Life expectancy ≥ 12 weeks
  9. Failure to respond to or refractory to approved/standard therapy; or for whom standard therapy does not exist, or is not tolerable; or for whom approved/standard therapy is not considered to be sufficient or appropriate by the Investigator.
  • Carboplatin Plus Paclitaxel Arm:
  -  Subjects who were previously treated with carboplatin and paclitaxel for locally advanced and/or metastatic disease and who received the last dose of the drug(s) ≥ 12 months prior to the first dose of the study treatment may be enrolled
  -  Subjects who were not previously treated with carboplatin and paclitaxel for locally advanced and/or metastatic disease and for whom, in the opinion of the Investigator, this chemotherapy regimen is appropriate may be enrolled
  • Paclitaxel Arm:
  -  Subjects who were previously treated with paclitaxel for locally advanced and/or metastatic disease and who in the opinion of the Investigator may benefit from the combination treatment of ARQ 092 and paclitaxel may be enrolled
  -  Subjects who were not previously treated with paclitaxel for locally advanced and/or metastatic disease and for whom, in the opinion of the Investigator, this chemotherapy regimen is appropriate may be enrolled
  10. 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 study treatment:
  -  Hematological
  -  Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (Carboplatin Plus Paclitaxel Arm or Paclitaxel Arm) or ≥ 1.0 x 109/L (Anastrozole Arm)
  -  Platelet count (Plt) ≥ 100 x 109/L
  -  Hemoglobin (Hb) ≥ 9 g/dL (Carboplatin Plus Paclitaxel Arm or Paclitaxel Arm) or ≥ 8 g/dL (Anastrozole Arm)
  -  Renal
  -  Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or
  -  Calculated creatinine clearance ≥ 60 mL/min /1.73 m2 for subjects with serum creatinine levels > 1.5 x institutional ULN
  -  Hepatic
  -  Total bilirubin ≤ 1.5 x ULN or
  -  Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 x ULN
  -  AST and ALT ≤ 3 x ULN or ≤ 5 x ULN for subjects with known liver metastases
  -  Metabolic
  -  Glycated hemoglobin (HbA1c) ≤ 8%
  11. If a subject is currently receiving bisphosphonates or denosumab, the subject must have received the bisphosphonates or denosumab for at least four weeks before starting study treatment. (Initiation of bisphosphonates or denosumab during the study may be allowed provided the subject completes the first cycle of treatment without any DLT and the Investigator rules out tumor progression.)
  12. Male or female subjects of child-bearing potential must agree to use double-barrier contraceptive measures, oral contraception, or avoidance of intercourse during and after the study (six months after the last dose of paclitaxel or 3 months after the last dose of ARQ 092 whichever is longer)
  Exclusion Criteria:
  1. Anti-cancer therapy, such as chemotherapy, immunotherapy, targeted and hormonal/endocrine therapy, or investigational agents within two weeks for oral drugs, four weeks for intravenous drugs, and six weeks for nitrosoureas, mitomycin C, or bevacizumab prior to administration of the first dose of study drug
  -  To be eligible for study treatment, toxicity from prior treatment must recover to Grade ≤ 1, except for alopecia
  -  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
  -  For subjects enrolled in the Carboplatin Plus Paclitaxel Arm or Paclitaxel Arm, 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 study treatment is allowed
  2. Radiation therapy within four weeks prior to administration of the first dose of study drug
  • To be eligible for study treatment, radiation therapy-related toxicity must recover to Grade ≤ 1 prior to administration of the first dose of study drug. Concurrent palliative radiotherapy for local pain-control may be allowed, provided the subject 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 study drug
  • To be eligible for study treatment, all surgical wounds must be fully healed and any surgery-related adverse events (AE) must recover to Grade ≤ 1
  4. Previous treatment with AKT inhibitors (e.g., MK-2206, GSK2141795, AZD5363)
  5. Contraindications to treatment with:
  -  Carboplatin and/or paclitaxel defined by the Investigator based on the Food and Drug Administration (FDA) approved labeling or institutional standard of care (SOC)
  -  Anastrozole defined by the Investigator based on institutional SOC, scientific evidence, expert medical judgment, or published literature
  6. History of allergic reaction attributed to compound(s) of similar chemical or biologic composition as ARQ 092, carboplatin, paclitaxel, or anastrozole
  7. Unable or unwilling to swallow ARQ 092 or anastrozole or comply with chemotherapy regimen
  8. Known active CNS metastases and/or carcinomatous meningitis
  • To be eligible for the study treatment, subjects must have stable disease ≥ 3 months, 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
  9. History of myocardial infarction (MI) or congestive heart failure defined as Class II to IV per the New York Heart Association (NYHA) classification within 6 months of the first dose of ARQ 092 (MI that occurred > 6 months prior to the first dose of ARQ 092 will be permitted)
  10. History of Type 1 or 2 diabetes mellitus requiring regular medication (other than oral hypoglycemic agents including metformin) or fasting glucose ≥ 160 mg/dL
  11. Significant gastrointestinal disorder(s), that could in the opinion of the Investigator, interfere with the absorption, metabolism, or excretion of ARQ 092 (e.g., Crohn's disease, ulcerative colitis, extensive gastric resection)
  12. Previous malignancy within 2 years of the first dose of study drugs, except tumors totally resected and/or not requiring therapy
  13. Concurrent uncontrolled illness not related to cancer, including but not limited to:
  • Ongoing or active infection, including human immunodeficiency virus (HIV), hepatitis B (HBV) (hepatitis B surface antigen [HBsAg] positive; subjects with documented laboratory evidence of HBV clearance may be enrolled) or hepatitis C (HCV) (positive HCV antibody), or bleeding
  14. Psychiatric illness, substance abuse, and/or social situation that would limit compliance with study requirements
  15. Blood transfusion within 5 days of the blood draw being used to confirm eligibility
  16. Pregnant or breastfeeding

Relevance to patient case: not relevant