Clinical trial NCT02476955: Open-label Phase 1b Study of ARQ 092 in Combination With Anastrozole
Official title: An Open-label Phase 1b Study of ARQ 092 in Combination With Other Antineoplastic Agents in Subjects With Selected Solid Tumors
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Solid Tumors
Ovarian Cancer
Endometrial Cancer
Keywords: ARQ 092
Carboplatin
Paclitaxel
AKT inhibitor in combination therapy
Targeted therapy
Molecular therapy
Tyrosine kinase inhibitor (TKI)
Receptor tyrosine kinase (RTK)
Biomarkers
Phase 1 - Phase I
Solid tumors
Metastatic solid tumors
Recurrent solid tumors
Ovarian cancer
Endometrial cancer
Cervical cancer
Triple-negative breast cancer
AKT kinases
AKT pathway
AKT signaling
AKT inhibitor
AKT pan inhibitor
Chemotherapy
PI3K/AKT/mTOR signaling pathway
AKT1
AKT2
AKT3
Phase I Clinical Trial
Clinical oncology
Tumor
AKT1 inhibitor
AKT2 inhibitor
AKT3 inhibitor
AKT1 mutation
AKT2 mutation
AKT3 mutation
AKT1 amplification
AKT2 amplification
AKT3 amplification
Anastrozole
Estrogen receptor positive
PIK3CA mutation
Lead sponsor: ArQule, Inc., a subsidiary of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ USA)
Sponsor class: INDUSTRY
First posted: 2015-06-22
Enrollment: 41
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: An Open-label Phase 1b Study of ARQ 092 in Combination with other Antineoplastic Agents 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.

Enrollment in the Carboplatin plus Paclitaxel Arm and Paclitaxel Alone Arm is now closed. Enrollment in the Expansion Cohort for the Anastrozole Arm continues for patients with Endometrial cancer.

Eligibility criteria: 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:

   * Subjects with endometrial cancer with:

     * Documented/locally determined AKT1, PIK3CA, or PIK3R1 mutations with or without PTEN deficiency
     * 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 requested amount of archival and/or fresh tissue biopsy samples at baseline for mutational analysis by the Sponsor's central laboratory.
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.
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) ≥ 1.0 x 109/L

      - Platelet count (Plt) ≥ 100 x 109/L

      - Hemoglobin (Hb) ≥ 8 g/dL
    * 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 (3 months after the last dose of ARQ 092 or anastrozole, whichever is longer)

Exclusion Criteria:

1. Anti-cancer therapy, such as chemotherapy, immunotherapy, targeted and hormonal/endocrine therapy, or investigational agents within five half-lives or two weeks (whichever is shorter) for oral drugs, five half-lives or four weeks (whichever is shorter) 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
   * Prior hormonal therapy (including, but not limited to, tamoxifen, megestrol acetate, fulvestrant, and GnRH analogs) for the treatment of recurrent/advanced endometrial cancer are not 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 anastrozole defined by the Investigator based on institutional Standard of Care (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 or anastrozole
7. Unable or unwilling to swallow ARQ 092 or anastrozole
8. Known active Central Nervous System (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

Primary outcomes:
measure: Number of treatment emergent adverse events (TEAEs) as assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03
timeFrame: Assessed at each scheduled visit up to treatment discontinuation + 30 days with an estimated treatment duration of 3 to 24 weeks
measure: Overall Response Rate (ORR) based on central review of tumor measurement using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
timeFrame: Baseline and every 2 cycles (8 weeks) after the first dose of ARQ 092 during the first 6 cycles (24 weeks) of treatment, and every 3 cycles (12 weeks) thereafter or as clinically indicated, and at the End of Treatment.
measure: Progression Free Survival (PFS) based on central review of tumor measurement using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
timeFrame: Baseline and every 2 cycles (8 weeks) after the first dose of ARQ 092 during the first 6 cycles (24 weeks) of treatment, and every 3 cycles (12 weeks) thereafter or as clinically indicated, and at the End of Treatment.
measure: Duration of Response (DoR) based on central review of tumor measurement
timeFrame: Baseline and every 2 cycles (8 weeks) after the first dose of ARQ 092 during the first 6 cycles (24 weeks) of treatment, and every 3 cycles (12 weeks) thereafter or as clinically indicated, and at the End of Treatment.
Secondary outcomes:
measure: Peak plasma concentration (Cmax)
timeFrame: During Cycle 1, Day 1 and Cycle 2, Day 1 of treatment (t=0, 2, 4, 6, 8, 10, 12 hours post ARQ 092 dose). And at Cycle 1, Day 8, Day 15, and Day 22 (t = pre-dose ARQ 092 dose).
measure: Area under the plasma concentration vs. time curve (AUC)
timeFrame: During Cycle 1, Day 1 and Cycle 2, Day 1 of treatment (t=0, 2, 4, 6, 8, 10, 12 hours post ARQ 092 dose). And at Cycle 1, Day 8, Day 15, and Day 22 (t = pre-dose ARQ 092 dose).
measure: Half-life of ARQ 092
timeFrame: During Cycle 1, Day 1 and Cycle 2, Day 1 of treatment (t=0, 2, 4, 6, 8, 10, 12 hours post ARQ 092 dose). And at Cycle 1, Day 8, Day 15, and Day 22 (t = pre-dose ARQ 092 dose).
Other outcomes:
Locations:
city: Grand Rapids
country: United States
state: Michigan
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
state: Texas
Study officials:
References: