Primary ObjectivesParts 1 and 2: To evaluate the safety and tolerability, describe any dose-limiting toxicity (DLT), determine the maximum tolerated dose (MTD) or highest protocol- defined doses (in the absence of exceeding the MTD) and the…
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Source
Brief title
Condition
- Other condition
Synonym
Health condition
Patients with Refractory Hematologic Malignancies or Solid Tumors
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The efficacy endpoints are the following:
• Objective response rate (ORR), defined as the percent of patients with
Complete Response (CR) or Partial Response (PR) according to RECIST
1.1 criteria or other standard malignancy-specific response criteria, relative
to the efficacy population.
• Duration of Response (DoR), defined as the time from documentation of tumor
response to disease progression
• Progression-Free Survival (PFS), defined as the time from study enrolment
until objective tumor progression or death
• Overall survival (OS), defined as the time from study entry to death from any
cause
Adverse events will be monitored during the period starting on the date
of receipt of first administration of 9-ING-41 and ending 30 days after
the final administration of 9 ING-41. All patients who receive any dose
(any amount) of 9-ING-41 or combination regimen will be included in
the summaries and listings of safety data. Overall safety profile and
tolerability will be characterized by type, frequency, severity, timing,
duration and relationship of study drug to adverse events and laboratory
abnormalities.
Secondary outcome
Specific secondary end points for patients with GBM or other CNS malignancies
will include progression free survival, landmark analyses for progression free
and overall survival, response rates according to the Response Assessment in
NeuroOncology (RANO) criteria, neurologic
deterioration-free survival (defined as the time from study entry to
documentation of neurologic deterioration or death), clinical or neurologic
deterioration-free survival, glucocorticoid use, the development of symptoms of
neurocognitive deterioration, and assessments of predictive factors.
Background summary
9-ING-41 is a first-in-class, intravenously (IV) administered, maleimide-based
small molecule potent selective GSK-3β inhibitor with significant pre-clinical
antitumor activity that involves G0-G1 and G2-M phase arrest. 9-ING-41 was
identified as a candidate therapeutic agent in chemoresistant human breast
cancer.
GSK-3 is a serine/threonine kinase initially described as a key regulator of
metabolism, specifically glycogen biosynthesis. It has a role in diverse
disease processes including cancer, immune disorders, metabolic disorders, and
neurological disorders through modulation of a large number of substrates.
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-*B) and c-Myc pathways as
well on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and
p53-mediated apoptotic mechanisms.
NF-*B is one of the most important transcription factors. Its activation is
essential in promoting human cancer progression, metastasis, and
chemoresistance. Among other relevant activities, GSK-3β helps maintain
malignant cell survival and proliferation, particularly in terms of mediating
resistance to standard anti-cancer therapies, through the NF-*B 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.
GSK-3β is a potentially very important therapeutic target in human
malignancies. This 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 objective
Primary Objectives
Parts 1 and 2: To evaluate the safety and tolerability, describe any
dose-limiting toxicity (DLT), determine the maximum tolerated dose (MTD) or
highest protocol- defined doses (in the absence of exceeding the MTD) and the
recommended Phase 2 study dose (RP2D) for 9-ING-41 as monotherapy (Study Part
1) and in combination with chemotherapies (Study Part 2) in patients with
relapsed or refractory malignancies.
Part 3: To assess clinical benefit in patients with relapsed or refractory
malignancies treated with 9-ING-41-based combinations at the RP2D established
in Part 2.
Secondary Objectives
1. To correlate response rates with specific molecular tumor profile(s) in a
descriptive fashion
Study design
Open label, non-randomized, international, multi-center, Phase 1/2.
Intervention
9-ING-41 is administered by intravenous infusion twice weekly. Cycle duration
is 21 days when administered as a single agent. When administered following a
companion chemotherapy agent, cycle duration is 21, 28 or -84 days depending
upon the chemotherapy agent.
In Parts 2 (RP2D finding) and 3 (Simon 2-Stage Phase 2 at the RP2D), 9-ING-41
will be administered following separate administration of the following:
• Gemcitabine 1250 mg/m2 as a 30-minute IV infusion on Days 1 and 8 of a 21-day
cycle
• Doxorubicin 75 mg/m2, IV bolus on Day 1 of a 21-day cycle up to a maximum
lifetime dose of 550 mg/m2
• Lomustine 30 mg/m² orally (PO) as a single dose, weekly for twelve weeks
• Carboplatin AUC 6 IV over 1 hour on Day 1 of a 21-day cycle
• Irinotecan 350 mg/m2 as a 90-minute IV infusion on Day 1 of a 21-day cycle
• Nab-paclitaxel 125 mg/m2 IV over 30-minutes immediately followed by
gemcitabine 1000 mg/m2 IV over 30-minutes on Days 1, 8 and 15 of a 28-day cycle
• Paclitaxel 175 mg/m2 IV over 3 hours immediately followed by carboplatin AUC
6 IV over 1 hour on Day 1 of a 21-day cycle
Study burden and risks
9-ING-41 is being tested in this clinical trial to explore if, when used alone
or in combination with chemotherapy there is an extension in the period where
the patient*s cancer is free of progression, and if the patient*s life is
extended. These benefits are possible but cannot be guaranteed. It is possible
that patient will receive no benefit from participating in the study.
Disadvantages of participation in the study may be:
• possible side effects/complications of the intervention
• possible adverse effects/discomforts of the evaluations in the study. Please
refer to section E9 "what risks does participation involve for human subjects"
for a detailed overview of the risks associated with the study drug or the
study procedures.
Participation in the study also means:
• additional time;
• additional or longer hospital stays;
• additional tests;
• instructions you need to follow;
• the study drug/study approach may not be better, and could possibly be worse,
than a different therapy for cancer treatment.
River Run, Suite 400 1751
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Age
Inclusion criteria
- 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
- Part 1&2: Has pathologically confirmed advanced or metastatic malignancy
characterized by one or more of the following:
a. Patient is intolerant of existing therapy(ies) known to provide clinical
benefit for their condition
b. Malignancy is refractory to existing therapy(ies) known to potentially
provide clinical benefit
c. Malignancy has relapsed after standard therapy
d. Malignancy for which there is no standard therapy that improves survival by
at least 3 months
- Part 3: Has pathologically confirmed advanced, recurrent, or metastatic
pancreatic cancer AND is previously untreated with systemic agents in the
advanced/metastatic setting.
- Has laboratory function within specified parameters (may be repeated):
a. Adequate bone marrow function: absolute neutrophil count (ANC) >= 500/mL;
hemoglobin >= 8.5 g/dL, platelets >= 50,000/mL (75,000/mL in Part 3)
b. Adequate liver function: transaminases (aspartate aminotransferase/ alanine
aminotransferase, AST/ALT) and alkaline phosphatase <= 3 (<= 10 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
c. Adequate renal function: creatinine clearance >= 30 mL/min (Cockcroft and
Gault), except for carboplatin/pemetrexed arm, which should be >= 45 mL/min
d. Serum amylase and lipase <= 1.5 x ULN
- Has adequate performance status (PS): Eastern Co-operative Oncology Group
(ECOG) PS 0-3
- 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:
• Chemotherapy, immunotherapy, or systemic radiation therapy - 14 days, or >= 5
half-lives (whichever is shorter) - Part 1&2
• Focal radiation therapy - 7 days
• Systemic and topical corticosteroids - 7 days - Part 1&2
• 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 - Part
1&2
- May have received treatment with fluorouracil or gemcitabine as a radiation
sensitizer in the adjuvant setting if the treatment was received at least 6
months before study enrollment - Part 3
- May have received neoadjuvant chemotherapy with FOLFIRINOX if given at least
6 months before study enrollment - Part 3
- May have received prior cytotoxic doses of systemic chemotherapy in the
adjuvant setting if given at least 6 months before study enrollment - Part 3
- 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
- For Part 1: Has as most recent prior anticancer therapy an immune checkpoint
agent (anti-PD-1, anti-PD-L1 or anti-CTLA-4), including, but not limited to:
pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, ipilimumab) and
had an inadequate response to that immune checkpoint therapy and/or Has a DNA
Repair Deficiency mutation confirmed by NGS in either tumor or blood.
and/or
Has acute T-cell leukemia/lymphoma (ATLL)
12. See Appendix Section 8.7 for details regarding Part 3 Arm B eligibility.
Exclusion criteria
- 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 endocrine or acinar pancreatic carcinoma - Part 3
- Has not recovered from clinically significant toxicities as a result of
prior anticancer therapy, except alopecia and infertility. Recovery is defined
as <= Grade 1 severity per Common Terminology Criteria for Adverse Events
(CTCAE) Version 4.03 (v 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 symptomatic rapidly progressive brain metastases or leptomeningeal
involvement as assessed by CT scan or MRI. Patients with stable 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 surgerymay 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
consideredmajor)
- 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)
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-003739-32-NL |
| ClinicalTrials.gov | NCT03678883 |
| CCMO | NL71462.031.19 |