9-ING-41 in Patients With Advanced Cancers

Sponsor

Actuate Therapeutics Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT03678883

Collaborator

(none)

350

Enrollment

Locations

Arms

57.9

Anticipated Duration (Months)

26.9

Patients Per Site

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Cancer Pancreatic Cancer Sarcoma Renal Cancer Refractory Cancer Refractory Neoplasm Refractory Non-Hodgkin Lymphoma Pancreatic Adenocarcinoma Resistant Cancer Neoplasm Metastasis Neoplasm of Bone Neoplasm, Breast Neoplasm of Lung Neoplasms,Colorectal Neoplasms Pancreatic Malignant Glioma Malignancies Malignancies Multiple Bone Metastases Bone Neoplasm Bone Cancer Pancreas Cancer Pancreatic Neoplasms Breast Neoplasms Acute T Cell Leukemia Lymphoma	Drug: 9-ING-41 Drug: Gemcitabine - 21 day cycle Drug: Doxorubicin. Drug: Lomustine Drug: Carboplatin. Drug: Nab paclitaxel. Drug: Paclitaxel. Drug: Gemcitabine - 28 day cycle Drug: Irinotecan	Phase 1/Phase 2

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 had three parts:

Completed: 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.
Completed: 9-ING-41 combined with standard anticancer agents: The 3+3 dose escalation study design will be used for 8 chemotherapy combination regimens (9-ING-41 plus gemcitabine, doxorubicin, lomustine, carboplatin, irinotecan, nab-paclitaxel plus gemcitabine, paclitaxel plus carboplatin, pemetrexed plus carboplatin) to identify the MTD/RP2D of each regimen.
Part 3: A randomized Phase 2 study of 9-ING-41 either once or twice weekly with gemcitabine and nab-paclitaxel (GA) versus GA alone for patients with previously untreated metastatic or locally advanced pancreatic cancer is now open.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

350 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jan 4, 2019

Anticipated Primary Completion Date :

Nov 1, 2022

Anticipated Study Completion Date :

Nov 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 9-ING-41 Drug: 9-ING-41	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.
Experimental: 9-ING-41 plus Gemcitabine Drugs: Gemcitabine - 21 day cycle. 9-ING-41	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 Other Names: Gemzar
Experimental: 9-ING-41 plus Doxorubicin Drugs: Doxorubicin. 9-ING-41	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: 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. Other Names: Doxil Adriamycin
Experimental: 9-ING-41 plus Lomustine Drugs: Lomustine. 9-ING-41.	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: Lomustine Lomustine 30 mg/m² orally as a single dose, weekly for twelve weeks. Other Names: CCNU Gleostine
Experimental: 9-ING-41 plus Carboplatin Drugs: Carboplatin. 9-ING-41.	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: Carboplatin. Carboplatin AUC 6 IV over 1 hour on Day 1 of a 21-day cycle. Other Names: Paraplatin
Experimental: 9-ING-41 plus nab paclitaxel Gemcitabine Drugs: Nab-paclitaxel. Gemcitabine - 28 day cycle. 9-ING-41.	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: Nab paclitaxel. Nab-paclitaxel 125 mg/m2 intravenously on Days 1, 8 and 15 of a 28-day cycle Other Names: Abraxane Protein-bound paclitaxel Nanoparticle albumin-bound paclitaxel Drug: Gemcitabine - 28 day cycle Gemcitabine 1000 mg/m2 intravenously over 30-minutes on Days 1, 8 and 15 of a 28-day cycle Other Names: Gemzar
Experimental: 9-ING-41 plus Paclitaxel/Carboplatin Drugs: Paclitaxel. Carboplatin. 9-ING-41.	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: Carboplatin. Carboplatin AUC 6 IV over 1 hour on Day 1 of a 21-day cycle. Other Names: Paraplatin Drug: Paclitaxel. Paclitaxel 175 mg/m2 intravenously over 3 hours on Day 1 of a 21-day cycle. Other Names: Taxol
Experimental: 9-ING-41 plus Irinotecan Drugs: Irinotecan. 9-ING-41.	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: Irinotecan Irinotecan 350 mg/m2 intravenously over 90-minutes on Day 1 of a 21-day cycle Other Names: Camptosar

Outcome Measures

Primary Outcome Measures

Parts 1/2: Number of participants with treatment-related adverse events as assessed by CTCAE v4.03 [3 months to 3 years]
The standard assessments used to assign a score to any affected organ system as per the NCI CTCAE 4.03 will be conduced at each protocol-specified timepoint.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patient -

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.
Is aged ≥ 18 years
Has pathologically confirmed advanced or metastatic malignancy characterized by one or more of the following:
Patient is intolerant of existing therapy(ies) known to provide clinical benefit for their condition
Malignancy is refractory to existing therapy(ies) known to potentially provide clinical benefit
Malignancy has relapsed after standard therapy
Malignancy for which there is no standard therapy that improves survival by at least 3 months
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.
Has laboratory function within specified parameters (may be repeated):
Adequate bone marrow function: absolute neutrophil count (ANC) ≥ 500/mL; hemoglobin ≥ 8.5 g/dL, platelets ≥ 50,000/mL
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
Adequate renal function: creatinine clearance ≥ 60 mL/min (Cockcroft and Gault)
Adequate blood coagulation: international normalized ratio (INR) ≤ 2.3
Serum amylase and lipase ≤ 1.5 x ULN
Has adequate performance status (PS): Eastern Co-operative Oncology Group (ECOG) PS 0-2
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

May continue endocrine therapies (e.g. for breast or prostate cancer) and/or anti-human epidermal growth factor (Her2) therapies while on this study
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
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
Must not be receiving any other investigational medicinal product

Exclusion Criteria:

Patient -

Is pregnant or lactating
Is known to be hypersensitive to any of the components of 9-ING-41 or to the excipients used in its formulation
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
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
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
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
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)
Has any medical and/or social condition which, in the opinion of the investigator or study medical coordinator would preclude study participation
Has received an investigational anti-cancer drug in the 14-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
Has a current active malignancy other than the target cancer
Is considered to be a member of a vulnerable population (for example, prisoners)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Phoenix	Arizona	United States	85054
2	UCSF Helen Diller Family Comprehensive Cancer Center	San Francisco	California	United States	94115
3	Miami Cancer Institute	Miami	Florida	United States	33176
4	Robert H. Lurie Comprehensive Cancer Center of Northwestern University	Chicago	Illinois	United States	60611
5	Kansas University Cancer Center	Kansas City	Kansas	United States	66160
6	University of Michigan	Ann Arbor	Michigan	United States	48109
7	Rhode Island Hospital	Providence	Rhode Island	United States	02903
8	Sanford Research	Sioux Falls	South Dakota	United States	57105
9	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee	United States	37232
10	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109
11	Netherlands Cancer Institute	Amsterdam		Netherlands	1066 CX
12	START Madrid-HM CIOCC Hospital Universitario	Madrid		Spain	28050
13	INCLIVA University of Valencia	Valencia		Spain	46010