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

• ClinicalTrials.gov Identifier: NCT02761694
• Recruitment Status: Recruiting
• First Posted: May 4, 2016
• Last Update Posted: October 30, 2019
• Sponsor: ArQule
• Information provided by (Responsible Party): ArQule

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Cancer; Solid Tumors	Drug: ARQ 751; Drug: ARQ 751 and fulvestrant; Drug: ARQ 751 and paclitaxel	Phase 1

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 100 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Study Start Date: June 2016
• Estimated Primary Completion Date: December 2020
• Estimated Study Completion Date: March 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: ARQ 751; Subjects will receive ARQ 751 orally 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.	Drug: ARQ 751; During dose escalation, subjects received ARQ 751 orally every day at dose levels specified for the respective dose cohort for a 28-day cycle During dose expansion, subjects will receive ARQ 751 orally at 75mg every day on a 28-day cycle.
Experimental: ARQ 751 and fulvestrant; ARQ 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.	Drug: ARQ 751 and fulvestrant; Subjects will receive ARQ 751 orally every day at dose levels specified for the respective dose cohort for a 28-day cycle in combination with fulvestrant (500 mg administered intramuscularly) on Days 1 & 15 of Cycle 1 and Day 1 on all subsequent cycles for each 28-day cycle.; Other Name: Faslodex
Experimental: ARQ 751 and paclitaxel; ARQ 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.	Drug: ARQ 751 and paclitaxel; ARQ 751 will be administered every day orally at dose levels specified for the respective dose cohort for a 28-day cycle in combination with an intravenous (IV) infusion of paclitaxel (80 mg/m2), once a week on Day 1, 8 &15 for three consecutive weeks followed by one week off of each 28-day cycle.; Other Name: Taxol

Outcome Measures

Primary Outcome Measures :

1. 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 ]
   The incidence of adverse events will be assessed as a measure of the safety and tolerability profile of ARQ 751

Secondary Outcome Measures :

1. 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) ]
2. 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) ]
3. 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) ]
4. 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 ]
5. Determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) of ARQ 751 as single agent and when given in combination with other anti-cancer treatments. [ Time Frame: Up to the first 28 days (1 cycle) of therapy ]
   MTD is defined as the dose level at which no more than one out of six subjects has an observable dose limiting toxicity (DLT)
6. 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 ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 AKT genetic alterations or known actionable PIK3CA/PTEN mutations by genetic testing

   • Subjects with tumors with PTEN null/PTEN loss-of-function mutations are not eligible

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

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

   • Subjects in single agent arm (with AKT genetic alterations) and subjects in dose escalation cohorts of combination therapy arms should have at least one line of standard systemic therapy
   • Subjects in single agent arm (with PIK3CA/PTEN actionable mutations) and subjects in the expansion cohorts of combination therapy arms should have no more than 3 prior systemic regimens for the advanced disease
   • 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 adequate contraception, including 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

   • 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 (for subjects considered for ARQ 751 +paclitaxel combination arm only)
6. 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
7. History of Type 1 diabetes mellitus or Type 2 diabetes mellitus requiring regular medication (other than oral hypoglycemic agents) or fasting glucose ≥ 160 mg/dL at Screening visit
8. 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)

9. 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

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 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)
11. A heart rate corrected QT (QTc) interval ≥ 480 msec, using the Fridericia's formula QTcF
12. 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

13. 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 (ARQ 751+paclitaxel combination arm)
    • Bleeding diathesis, thrombocytopenia or coagulation disorders (ARQ 751+fulvestrant combination arm)
    • Thrombotic/coagulation disorders within 6 months prior to the first dose of study treatment unless stable on anticoagulation for > 3 months
14. 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
15. Blood transfusion or administration of growth factors within 5 days prior to a blood draw being used to confirm eligibility
16. Pregnant or breastfeeding

Contacts and Locations

Contacts

Contact: ArQule, Inc.; 781-994-0300; ClinicalTrials@arqule.com

Locations

United States, Nevada

Completed

Las Vegas, Nevada, United States, 89169

United States, Oklahoma

Stephenson Cancer Center; Recruiting

Oklahoma City, Oklahoma, United States, 73104

Contact: ArQule, Inc. 781-994-0300 ClinicalTrials@arqule.com

United States, South Carolina

Charleston Hematology Oncology; Recruiting

Charleston, South Carolina, United States, 29414

Contact: ArQule 781-994-0300 ClinicalTrials@arqule.com

United States, Tennessee

The Sarah Cannon Research Institute; Recruiting

Nashville, Tennessee, United States, 37203

Contact: ArQule, Inc. 781-994-0300 ClinicalTrials@arqule.com

United States, Texas

Mary Crowley Cancer Research; Recruiting

Dallas, Texas, United States, 75230

Contact: ArQule, Inc. 781-994-0300 ClinicalTrials@arqule.com

MD Anderson Cancer Center; Recruiting

Houston, Texas, United States, 77030

Contact: ArQule, Inc. 781-994-0300 ClinicalTrials@arqule.com

Sponsors and Collaborators

ArQule

Investigators

• Study Director: Brian Schwartz, MD; ArQule

More Information

• Responsible Party: ArQule
• ClinicalTrials.gov Identifier: NCT02761694
• Other Study ID Numbers: ARQ 751-101
• First Posted: May 4, 2016
• Last Update Posted: October 30, 2019
• Last Verified: October 2019

Keywords provided by ArQule:

AKT1; AKT2; AKT3; PI3K; solid tumors; cancer; ARQ 751; ArQule; PTEN

Additional relevant MeSH terms:

Neoplasms; Paclitaxel; Albumin-Bound Paclitaxel; Fulvestrant; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Hormonal; Estrogen Receptor Antagonists; Estrogen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs