Patient case: 45-year-old female with colon cancer; genetic feature: ERBB2 amplification

Clinical trial: 9-ING-41 in Patients With Advanced Cancers

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.

Detailed description: 9-ING-41 is a first-in-class, intravenously administered, maleimide-based small molecule potent selective GSK-3β inhibitor with significant pre-clinical antitumor activity. GSK-3 is a serine/threonine kinase initially described as a key regulator of metabolism and has a role in diverse disease processes including cancer, immune disorders, pathologic fibrosis, metabolic disorders, and neurological disorders. GSK-3 has two ubiquitously expressed and highly conserved isoforms, GSK-3α and GSK-3β, with both shared and distinct substrates and functional effects. GSK-3β is particularly important in tumor progression and modulation of oncogenes (including beta-catenin, cyclin D1 and c-Myc), cell cycle regulators (e.g. p27Kip1) and mediators of epithelial-mesenchymal transition (e.g. zinc finger protein SNAI1, Snail). Aberrant overexpression of GSK-3β has been shown to promote tumor growth and chemotherapy resistance in various solid tumors including colon, ovarian, and pancreatic cancers and glioblastoma through differential effects on the pro-survival nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and c-Myc pathways as well on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and p53-mediated apoptotic mechanisms. GSK-3β helps maintain malignant cell survival and proliferation, particularly in terms of mediating resistance to standard anti-cancer therapies, through the NF-κB pathway. GSK-3β has been established as a potential anticancer target in human bladder, breast, colorectal, glioblastoma, lung, neuroblastoma, ovarian, pancreatic, prostate, renal and thyroid cancers as well as chronic lymphocytic leukemia and lymphomas.
  9-ING-41 is a small molecule potent selective GSK-3β inhibitor with broad spectrum pre-clinical antitumor activity. It's modes of action include downregulation of NF-κB and decreasing the expression NF-κB target genes including cyclin D1, Bcl-2, anti-apoptotic protein (XIAP) and B-cell lymphoma-extra large (Bcl-XL) leading to inhibition of tumor growth in multiple solid tumor cell and lymphoma lines and patient derived xenograft (PDX) models. NF-κB is constitutively active in cancer cells and promotes anti-apoptotic molecule expression. NF-κB activation is particularly important in cancer cells that have become chemo- and/or radio-resistant. 9-ING-41 also has significant activity in pre-clinical models of pathological pleural and pulmonary fibrosis. 9-ING-41 has significant in vitro and in vivo activity as a single agent and/or in combination with standard cytotoxic chemotherapies in a spectrum of solid tumors and hematological malignancies including bladder, breast, glioblastoma, neuroblastoma, pancreatic, sarcomas, and renal cancers as well as lymphomas.
  The 1801 study will have three parts:
  -  Part 1 (9-ING-41 as monotherapy): The standard 3+3 dose escalation design will be applied to all dose cohorts until the Maximum Tolerated Dose (MTD) or Recommended Phase 2 Dose (RP2D) is identified
  -  Part 2: 9-ING-41 combined with standard anticancer agents: The 3+3 dose escalation study design will be used for 6 chemotherapy combination regimens (9-ING-41 plus gemcitabine, doxorubicin, lomustine, carboplatin, nab-paclitaxel plus gemcitabine, paclitaxel plus carboplatin) to identify the MTD/RP2D of each regimen. Part 2 will be started after a maximum of 3 dose escalations of 9-ING-41 as a single agent in Part 1. The starting dose level in Part 2 of 9-ING-41 within the six combination regimens will be the 3rd dose level of single agent 9-ING-41 (or lower if the IDMC so recommends). Dose escalations of 9-ING-41 as a single agent in Part 1 will continue in parallel with dose escalations of 9-ING-41 in combination treatments in Part 2.
  -  Part 3: Assessment of activity of 9-ING-41 based combination regimens: The primary objective for Study Part 3 is to assess the clinical benefit of each of the six 9-ING-41-based combination regimens. Secondary objectives will include the assessment of other efficacy variables, including progression-free survival (PFS), duration of tumor response, time to treatment failure, 1-year survival rate and overall survival (OS) as well as additional evaluation of toxicities. The Simon's 2-stage design will be employed for Study Part 3 for the six 9-ING-41-based combination regimens.

Eligibility: 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) ≥ 1,000/mL; hemoglobin ≥ 8.5 g/dL, platelets ≥ 75,000/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 0-1
  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 - 21 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
  12. For study Parts 2 and 3, must have received prior therapy for the same malignancy including the same potential partner agent(s) as that/those being considered for administration on study in combination with 9-ING-41
  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 ≤ 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 anticonvulsants and steroids are at a stable dose for a period of 14 days prior to the first dose of study drug
  7. Has had major surgery (not including placement of central lines) within 7 days prior to study entry or is planned to have major surgery during the course of the study (major surgery may be defined as any invasive operative procedure in which an extensive resection is performed, e.g. a body cavity is entered, organs are removed, or normal anatomy is altered. In general, if a mesenchymal barrier is opened (pleural cavity, peritoneum, meninges), the surgery is considered major)
  8. Has any medical and/or social condition which, in the opinion of the investigator or study medical coordinator would preclude study participation
  9. Has received an investigational anti-cancer drug in the 21-day period before the first dose of study drug (or within 5 half-lives if longer) or is currently participating in another interventional clinical trial
  10. Has had a previous (within 2 years) or has a current malignancy other than the target cancer with the exception of curatively treated local tumors including carcinoma in situ of the breast or cervix, basal or squamous cell carcinoma of the skin, or prostate cancer with Gleason Grade < 6 and prostate-specific antigen within normal range
  11. Is considered to be a member of a vulnerable population (for example, prisoners)
  12. For Study Parts 2 and 3, must not have developed persistent (>28 days) clinically significant Grade 3/4 toxicities attributable to same prior chemotherapy agent as that being considered for administration on this study in combination with 9-ING-41
  13. During Parts 1 and 2 of the study, patients taking strong inhibitors of CYP2C19, CYP3A4, and CYP1A2 or strong inducers of CYP3A4 should not be entered into the study protocol; this will be reviewed by the IDMC prior to Part 3 of the study opening to recruitment

Relevance to patient case: not relevant