Clinical Trials /

ARQ 751 as a Single Agent or in Combination With Other Anti-Cancer Agents, in Solid Tumors With PIK3CA / AKT / PTEN Mutations

NCT02761694

Description:

An open-label, Phase 1b, study of ARQ 751 as a single agent or in combination with other anti-cancer agents, in subjects with advanced solid tumors with PIK3CA / AKT / PTEN mutations.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: ARQ 751 as a Single Agent or in Combination With Other Anti-Cancer Agents, in Solid Tumors With PIK3CA / AKT / PTEN Mutations
  • Official Title: A Phase 1b Study of ARQ 751 as a Single Agent or in Combination With Other Anti-Cancer Agents in Adult Subjects With Advanced Solid Tumors With PIK3CA / AKT / PTEN Mutations

Clinical Trial IDs

  • ORG STUDY ID: ARQ 751-101
  • NCT ID: NCT02761694

Conditions

  • Cancer
  • Solid Tumors

Interventions

DrugSynonymsArms
ARQ 751ARQ 751
ARQ 751 and fulvestrantFaslodexARQ 751 and fulvestrant
ARQ 751 and paclitaxelTaxolARQ 751 and paclitaxel

Purpose

An open-label, Phase 1b, study of ARQ 751 as a single agent or in combination with other anti-cancer agents, in subjects with advanced solid tumors with PIK3CA / AKT / PTEN mutations.

Detailed Description

      AKT inhibitor may decrease or arrest growth of cancer cells that depends on the presence of a
      protein called AKT. A number of genes, namely, PIK3CA, AKT and PTEN, may cause the AKT to
      behave abnormally, so by blocking the action of these genes on AKT with the drug like ARQ
      751, the cancer spread may be stopped or slowed down. Paclitaxel and fulvestrant are standard
      anticancer agents, paclitaxel is given to destroy cancer cells and fulvestrant to lower the
      amount of estrogen the body makes. ARQ 751 in combination with paclitaxel or fulvestrant may
      potentiate effect of a single therapy in tumors driven by PIK3CA/AKT/PTEN mutations.
    

Trial Arms

NameTypeDescriptionInterventions
ARQ 751ExperimentalSubjects will receive ARQ 751 orally at 75mg every day. Subjects will receive treatment with ARQ 751 until unacceptable toxicity, disease progression (clinical or radiological), or another of the discontinuation criteria is documented. It is expected that most subjects will receive between one and six cycles of ARQ 751 for a treatment period of 4 to 24 weeks.
  • ARQ 751
ARQ 751 and fulvestrantExperimentalARQ 751 will be administered orally every day (QD) of a 28-day cycle in combination with fulvestrant, which will be administered intramuscularly on Days 1 & 15 of Cycle 1 and Day 1 of all subsequent cycles. The combination treatment will continue until progression of disease (clinical or radiological), unacceptable toxicity, or another of the discontinuation criteria is documented.
  • ARQ 751 and fulvestrant
ARQ 751 and paclitaxelExperimentalARQ 751 will be administered orally every day of a 28-day cycle in combination with paclitaxel, which will be administered intravenously on Days 1, 8 & 15 of each cycle. The combination treatment will continue until progression of disease (clinical or radiological), unacceptable toxicity, or another of the discontinuation criteria is documented.
  • ARQ 751 and paclitaxel

Eligibility Criteria

        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 and/or cytologically documented diagnosis of a selected tumor type that
             is locally advanced, inoperable, metastatic or recurrent (including but not restricted
             to breast cancer, TNBC [triple negative]; HR-positive [HR+]/HER2-negative [HER2-] or
             endometrial cancer)

          4. Documented PIK3CA, AKT or known actionable PTEN mutations by genetic testing

          5. For combination arms; eligible for paclitaxel or fulvestrant therapy as per
             Investigator assessment

          6. Failure to respond to standard therapy, or for whom standard or curative therapy does
             not exist or is not tolerable

               -  No more than 3 prior systemic regimens for the advanced disease with confirmed
                  disease progression

               -  Neoadjuvant and adjuvant chemotherapy are considered one regimen if they are a
                  continuation of the same regimen with interval debulking surgery

               -  If the subject is refractory or has disease progression within 6 months after
                  completion of the adjuvant treatment, then the adjuvant treatment should be
                  considered as the line of treatment rather than an adjuvant therapy.

               -  Endocrine (hormonal) therapy does not count toward total lines of therapy

               -  Maintenance therapy is considered part of the preceding regimen if one or more of
                  the same drugs are continued

          7. Has at least one measurable target lesion according to RECIST v. 1.1

          8. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1

          9. Adequate organ function as indicated by the following laboratory values. (All
             laboratory tests must be obtained within 14 days prior to the first dose of study
             treatment):

               1. Hematological

                    -  Absolute neutrophil count (ANC) ≥ 1.5 x 10⁹/L

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

                    -  Hemoglobin (Hb) ≥ 9 g/dL

                    -  International normalized ratio (INR) 0.8 to upper limit of normal (ULN) or ≤
                       3 for subjects receiving anticoagulant therapy such as Coumadin or heparin

               2. Renal

                    -  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

               3. Hepatic

                    -  Total bilirubin ≤ 1.5 x ULN

                    -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x
                       ULN or ≤ 5 x ULN for subjects with known liver metastases

               4. Metabolic

                    -  Glycated hemoglobin (HbA1c) ≤ 8% (≤ 64 mmol/mol)

         10. If a subject is currently receiving bisphosphonates or any other drug for treatment of
             osteoporosis, treatment-induced bone loss and metastases to bone, the subject must
             have received the bisphosphonates for at least four weeks prior to the first dose of
             study treatment

             • Initiation of bisphosphonates or similar agents 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

         11. 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 study treatment

         12. Women of childbearing potential must have a negative serum pregnancy test. "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 study treatment

        Exclusion Criteria

          1. Anti-cancer therapy, such as chemotherapy, immunotherapy, hormonal therapy, targeted
             therapy, or investigational agents within five half-lives or four weeks, whichever is
             shorter, prior to administration of the first dose of study treatment (five half-lives
             or six weeks, whichever is shorter)

               -  To be eligible for study treatment, toxicity from prior treatment(s) must recover
                  to Grade ≤ 1, except for alopecia

               -  Concurrent systemic high-dose corticosteroids (in dosing exceeding 10 mg QD of
                  prednisone equivalent) when used intermittently in an antiemetic regimen, for
                  central nervous system (CNS) metastases management, or as a part of the
                  premedication regimen are allowed

          2. Radiation therapy within four weeks, or palliative radiation therapy within two weeks,
             prior to administration of the first dose of study treatment

               -  To be eligible for study treatment, radiation therapy-related toxicity must
                  recover to Grade ≤ 1 prior to administration of the first dose of study treatment

               -  Concurrent palliative radiotherapy for local pain-control or prevention of
                  fracture (for known bone metastases) 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 study treatment

             • 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. Unable or unwilling to swallow the complete daily dose of ARQ 751

          5. Previous treatment with

               -  AKT inhibitors (e.g., ARQ 092, MK-2206, GSK2141795, AZD5363; prior treatment with
                  PI3K or mTOR inhibitor are allowed)

               -  Prior taxane therapy for the advanced, metastatic disease

               -  Known prior allergic reaction to or severe intolerance of paclitaxel or
                  fulvestrant. Intolerance is defined as a serious adverse event, a grade 3 or 4 AE
                  per CTCAE v.4.03, or permanent treatment discontinuation

          6. History of Type 1 or 2 diabetes mellitus requiring regular medication (other than oral
             hypoglycemic agents) or fasting glucose ≥ 160 mg/dL at Screening visit

          7. Significant gastrointestinal disorder(s) that could, in the opinion of the
             Investigator, interfere with the absorption, metabolism, or excretion of ARQ 751
             (e.g., inflammatory bowel disease, Crohn's disease, ulcerative colitis, extensive
             gastric resection)

          8. Known untreated or active CNS metastases and/or carcinomatous meningitis

             • 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

          9. 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
             study treatment (MI occurring > 6 months of the first dose of study treatment will be
             permitted); Grade 2 or worse conduction defect (e.g., right or left bundle branch
             block)

         10. A heart rate corrected QT (QTc) interval ≥ 480 msec, using the Fridericia's formula
             QTcF

         11. Left ventricular ejection fraction (LVEF) <50% as determined by Multiple Gated
             Acquisition (MUGA) scan or echocardiogram (ECHO) in subjects who received prior
             treatment with anthracyclines

         12. Concurrent severe and/or uncontrolled illness not related to cancer and/or social
             situation that would limit compliance with study requirements, including but not
             limited to:

               -  Psychiatric illness, substance abuse

               -  Ongoing or active known infection, including human immunodeficiency virus (HIV)
                  infection, hepatitis B or C virus

               -  Significant pulmonary dysfunction, including pneumonitis, interstitial lung
                  disease (ILD), idiopathic pulmonary fibrosis, cystic fibrosis, severe COPD

               -  Peripheral neuropathy grade ≥2 (Arm B, ARQ 751+paclitaxel)

               -  Bleeding diathesis, thrombocytopenia or coagulation disorders (Arm C, ARQ
                  751+fulvestrant)

               -  Thrombotic/coagulation disorders within 6 months prior to the first dose of study
                  treatment unless stable on anticoagulation for > 3 months

         13. Active or history of other malignancy other than the current cancer within 2 years of
             the first dose of study treatment, with the exception of carcinoma in-situ of the
             cervix, basal cell carcinoma, and superficial bladder tumors curatively treated

         14. Blood transfusion or administration of growth factors within 5 days prior to a blood
             draw being used to confirm eligibility

         15. Pregnant or breastfeeding
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) guidelines v4.03
Time Frame:Up to 24 weeks
Safety Issue:
Description:The incidence of adverse events will be assessed as a measure of the safety and tolerability profile of ARQ 751

Secondary Outcome Measures

Measure:Assess the peak plasma concentration (Cmax) of the pharmacokinetic (PK) profile of ARQ 751
Time Frame:Cycle 1 Day 1 (C1D1) (each cycle is 28 days) (time [t]=0,1,2,4,6,8 hours [h]), C1D2 (t=0), and C1D15 (t=0,1,2 h), C2D1 (t=0,1,2,4,6,8 h), C2D2 (t=0), C3D1 (t=0,1,2 h), C4D1 (t=0,1,2 h)
Safety Issue:
Description:
Measure:Assess the area under the plasma concentration vs. time curve (AUC) of the pharmacokinetic (PK) profile of ARQ 751
Time Frame:Cycle 1 Day 1 (C1D1) (each cycle is 28 days) (time [t]=0,1,2,4,6,8 hours [h]), C1D2 (t=0), and C1D15 (t=0,1,2 h), C2D1 (t=0,1,2,4,6,8 h), C2D2 (t=0), C3D1 (t=0,1,2 h), C4D1 (t=0,1,2 h)
Safety Issue:
Description:
Measure:Assess the half life of ARQ 751 of the pharmacokinetic (PK) profile of ARQ 751
Time Frame:Cycle 1 Day 1 (C1D1) (each cycle is 28 days) (time [t]=0,1,2,4,6,8 hours [h]), C1D2 (t=0), and C1D15 (t=0,1,2 h), C2D1 (t=0,1,2,4,6,8 h), C2D2 (t=0), C3D1 (t=0,1,2 h), C4D1 (t=0,1,2 h)
Safety Issue:
Description:
Measure:Assess changes in serum glucose, insulin and cell-free ctDNA, to determine pharmacodynamic activity of ARQ 751
Time Frame:Blood samples are collected on Day 1 of Cycles 1, 2, and 3 (each cycle is 28 days) and at the End of Treatment visit, which may occur at up to 24 weeks after the first dose
Safety Issue:
Description:
Measure:Determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) of ARQ 751 when given in combination with other anti-cancer treatments.
Time Frame:Up to the first 28 days (1 cycle) of therapy
Safety Issue:
Description:MTD is defined as the dose level at which no more than one out of six subjects has an observable dose limiting toxicity (DLT)
Measure:Evaluate tumor response assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 after treatment with ARQ 751
Time Frame:Tumor assessments will be performed at Baseline, every eight weeks (e.g., Cycle 3 Day 1, Cycle 5 Day 1, etc), and at the End of Treatment visit, which may occur at up to 24 weeks after the first dose
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:ArQule

Trial Keywords

  • AKT1
  • AKT2
  • AKT3
  • PI3K
  • PTEN-null
  • solid tumors
  • cancer
  • ARQ 751
  • ArQule
  • PTEN

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