Phase 1/2 Study of 9-ING-41, a Glycogen Synthase Kinase-3 Beta (GSK-3β) Inhibitor, as a Single Agent and Combined With Chemotherapy, in Patients With Refractory Hematologic Malignancies or Solid Tumors

Official Summary

GSK-3β is a potentially important therapeutic target in human malignancies. The Actuate 1801 Phase 1/2 study is designed to evaluate the safety and efficacy of 9-ING-41, a potent GSK-3β inhibitor, as a single agent and in combination with cytotoxic agents, in patients with refractory cancers.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: NONE
• Enrollment: 350 participants

Interventions

• DRUG: 9-ING-41 — Starting dose of-9-ING-41 will be administered on Day 1 and 4 each week of a 21-day cycle. 9-ING-41 will be administered intravenously over 60 minutes.
• DRUG: Gemcitabine - 21 day cycle — Gemcitabine 1250 mg/m2 as a 30-minute intravenous infusion on Days 1 and 8 of a 21-day cycle
• DRUG: Doxorubicin. — Doxorubicin 75 mg/m2, intravenous bolus on Day 1 of a 21-day cycle up to a maximum lifetime dose of 550 mg/m2.
• DRUG: Lomustine — Lomustine 30 mg/m² orally as a single dose, weekly for twelve weeks.
• DRUG: Carboplatin. — Carboplatin AUC 6 IV over 1 hour on Day 1 of a 21-day cycle.

Primary Outcomes

• Parts 1/2: Number of participants with treatment-related adverse events as assessed by CTCAE v4.03 (3 months to 3 years)
• Part 3 Arm B (3 months to 3 years)

Eligibility Criteria

Inclusion Criteria:

* Patient -

  1. Is able to understand and voluntarily sign a written informed consent and is willing and able to comply with the protocol requirements including scheduled visits, treatment plan, laboratory tests and other study procedures.
  2. Is aged ≥ 18 years
  3. Has pathologically confirmed advanced or metastatic malignancy characterized by one or more of the following:

     1. Patient is intolerant of existing therapy(ies) known to provide clinical benefit for their condition
     2. Malignancy is refractory to existing therapy(ies) known to potentially provide clinical benefit
     3. Malignancy has relapsed after standard therapy
     4. Malignancy for which there is no standard therapy that improves survival by at least 3 months
  4. Has evaluable tumor(s) by standard radiological and/or laboratory assessments as applicable to their malignancy - in Part 3, patients with solid tumors must have least 1 measurable lesion per response evaluation criteria in solid tumors (RECIST) v1.1 criteria, measured preferably by computed tomography (CT) scan or magnetic resonance image (MRI). In the case of patients with glioblastoma multiforme (GBM) or other central nervous system (CNS) tumors, the tumor must be measurable, defined as a clearly enhancing tumor with at two perpendicular diameters at entry equal or superior to 1cm.
  5. Has laboratory function within specified parameters (may be repeated):

     1. Adequate bone marrow function: absolute neutrophil count (ANC) ≥ 500/mL; hemoglobin ≥ 8.5 g/dL, platelets ≥ 50,000/mL
     2. Adequate liver function: transaminases (aspartate aminotransferase/ alanine aminotransferase, AST/ALT) and alkaline phosphatase ≤ 3 (≤ 5 X the upper limit of normal (ULN) in the setting of liver metastasis or infiltration with malignant cells) x ULN; bilirubin ≤ 1.5 x ULN
     3. Adequate renal function: creatinine clearance ≥ 60 mL/min (Cockcroft and Gault)
     4. Adequate blood coagulation: international normalized ratio (INR) ≤ 2.3
     5. Serum amylase and lipase ≤ 1.5 x ULN
  6. Has adequate performance status (PS): Eastern Co-operative Oncology Group (ECOG) PS 0-2
  7. Has received the final dose of any of the following treatments/ procedures with the specified minimum intervals before first dose of study drug (unless in the opinion of the investigator and the study medical coordinator the treatments/ procedures will not compromise patient safety or interfere with study conduct and with IDMC agreement):

     * Chemotherapy, immunotherapy, or systemic radiation therapy - 14 days or ≥ 5 half-lives (whichever is shorter)
     * Focal radiation therapy - 7 days
     * Systemic and topical corticosteroids - 7 days
     * Surgery with general anesthesia - 7 days
     * Surgery with local anesthesia - 3 days
  8. May continue endocrine therapies (e.g. for breast or prostate cancer) and/or anti-human epidermal growth factor (Her2) therapies while on this study
  9. Women of childbearing potential must have a negative baseline blood or urine pregnancy test within 72 hours of first study therapy. Women may be neither breastfeeding nor intending to become pregnant during study participation and must agree to use effective contraceptive methods (hormonal or barrier method of birth control, or true abstinence) for the duration of study participation and in the following 90 days after discontinuation of study treatment
  10. Male patients with partners of childbearing potential must take appropriate precautions to avoid fathering a child from screening until 90 days after discontinuation of study treatment and use appropriate barrier contraception or true abstinence
  11. Must not be receiving any other investigational medicinal product

Exclusion Criteria:

* Patient -

  1. Is pregnant or lactating
  2. Is known to be hypersensitive to any of the components of 9-ING-41 or to the excipients used in its formulation
  3. Has not recovered from clinically significant toxicities as a result of prior anticancer therapy, except alopecia and infertility. Recovery is defined as ≤ Grade 2 CTCAE Version 4.03
  4. Has significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, or stroke within 6 months of the first dose of 9-ING-41, or cardiac arrhythmia requiring medical treatment detected at screening
  5. Has had a myocardial infarction within 12 weeks of the first dose of 9-ING-41 or has electrocardiogram (ECG) abnormalities that are deemed medically relevant by the investigator or study medical coordinator
  6. Has known symptomatic rapidly progressive brain metastases or leptomeningeal involvement as assessed by CT scan or MRI. Patients with stable asymptomatic brain metastases or leptomeningeal disease or slowly progressive disease are eligible provided that they have not required new treatments for this disease in a 28-day period before the first dose of study drug, and anticon

Trial Locations

• Mayo Clinic, Phoenix, Arizona, United States
• Arizona Oncology Associates, Tucson, Arizona, United States
• The University of Arizona Cancer Center, Tucson, Arizona, United States
• University of California Irvine Health, Orange, California, United States
• UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California, United States
• Christiana Care Health Services, Newark, Delaware, United States
• Sibley Memorial Hospital, Washington D.C., District of Columbia, United States
• Florida Cancer Specialists - South, Fort Myers, Florida, United States
• Miami Cancer Institute, Miami, Florida, United States
• Florida Cancer Specialists - North, St. Petersburg, Florida, United States
• ...and 10 more locations

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