CHK1 Inhibitor for Lung Cancer
(POTENTIATE Trial)
Recruiting in Palo Alto (17 mi)
+15 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Boundless Bio
Must not be taking: CHK1 inhibitors, EGFR inhibitors, FGFR inhibitors
Disqualifiers: Hematologic malignancies, CNS malignancy, HBV, others
No Placebo Group
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?BBI-355 is an oral, potent, selective checkpoint kinase 1 (or CHK1) small molecule inhibitor in development as an ecDNA (extrachromosomal DNA) directed therapy (ecDTx). This is a first-in-human, open-label, 3-part, Phase 1/2 study to determine the safety profile and identify the maximum tolerated dose and recommended Phase 2 dose of BBI-355 administered as a single agent or in combination with select therapies.
Will I have to stop taking my current medications?
The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.
Is the CHK1 inhibitor BBI-355 safe for humans?
Some studies on CHK1 inhibitors suggest they can be used safely in combination with other treatments, as they showed no toxicity in mice when combined with another inhibitor. However, there have been challenges with off-target toxicities in some CHK1 inhibitors, which means they might affect other parts of the body unintentionally.
12345What makes the drug BBI-355 unique for lung cancer treatment?
BBI-355 is a CHK1 inhibitor that targets the DNA damage response, making it unique by preventing cancer cells from repairing damaged DNA and progressing through the cell cycle. This mechanism can enhance the effectiveness of existing chemotherapy and also offers potential as a standalone treatment.
45678Eligibility Criteria
This trial is for adults with advanced solid tumors like lung, stomach, or breast cancer that's worsened after standard treatments. Participants must have evidence of oncogene amplification and measurable disease. They should be in good physical condition (ECOG PS 0 or 1) and have proper organ function. People with primary brain cancers, certain heart conditions, active hepatitis B/C or HIV, a history of severe lung issues, or those who've had specific transplants can't join.Inclusion Criteria
My cancer has spread, doesn't respond to treatment, and can't be surgically removed.
My cancer shows gene changes that make it grow faster.
My cancer shows a high level of normal EGFR.
+7 more
Exclusion Criteria
I have had cancer before, but it fits the study's exceptions.
My cancer has specific gene changes known to help it grow.
Other exclusion criteria per study protocol
+10 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Dose Escalation
Single agent BBI-355 or combination therapy with EGFR or FGFR inhibitors is administered in 28-day cycles to determine the maximum tolerated dose and recommended Phase 2 dose.
28 days per cycle
Dose Expansion
BBI-355 is administered as a single agent in 28-day cycles to further evaluate safety and efficacy.
28 days per cycle
Follow-up
Participants are monitored for safety and effectiveness after treatment, including assessment of treatment emergent adverse events.
30 days following last dose
Participant Groups
The study tests BBI-355 as a new treatment targeting ecDNA in tumors. It's an early-phase trial to find the safest dose when given alone or with other therapies. The drug is taken orally and aims to inhibit CHK1—a protein involved in tumor cell growth.
4Treatment groups
Experimental Treatment
Group I: Single Agent Dose ExpansionExperimental Treatment1 Intervention
Single agent BBI-355, administered orally in 28-day cycles
Group II: Single Agent Dose EscalationExperimental Treatment1 Intervention
Single agent BBI-355, administered orally in 28-day cycles
Group III: Dose Escalation in Combination with FGFR InhibitorExperimental Treatment2 Interventions
Combination therapy of BBI-355 and FGFR1-4 inhibitor futibatinib, administered orally in 28-day cycles.
Group IV: Dose Escalation in Combination with EGFR InhibitorExperimental Treatment2 Interventions
Combination therapy of BBI-355 and EGFR inhibitor erlotinib, administered orally in 28-day cycles.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Medical University of South CarolinaCharleston, SC
NEXT Oncology - DallasIrving, TX
University of WisconsinMadison, WI
Dana Farber Cancer InstituteBoston, MA
More Trial Locations
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Who Is Running the Clinical Trial?
Boundless BioLead Sponsor
References
An orally bioavailable Chk1 inhibitor, CCT244747, sensitizes bladder and head and neck cancer cell lines to radiation. [2022]Chk1 inhibition increases cell sensitivity to both chemotherapy and radiotherapy in several tumour types and is, therefore, a promising anti-cancer approach. Although several Chk1 inhibitors have been developed, their clinical progress has been hampered by low bioavailability and off-target toxicities.
Combined inhibition of Chk1 and Wee1: in vitro synergistic effect translates to tumor growth inhibition in vivo. [2020]Targeting Chk1 protein kinase can enhance the antitumor effects of radio- and chemotherapy. Recent evidence disclosed a role of Chk1 in unperturbed cell proliferation and survival, implying that Chk1 inhibitors could also be effective as single agents in tumors with a specific genetic background. To identify genes in synthetic lethality with Chk1, we did a high-throughput screening using a siRNA library directed against 719 human protein kinases in the human ovarian cancer cell line OVCAR-5, resistant to Chk1 inhibitors. Wee1 tyrosine kinase was the most significant gene in synthetic lethality with Chk1. Treatment with non-toxic concentrations of a Chk1 inhibitor (PF-00477736) and a Wee1 inhibitor (MK-1775) confirmed the marked synergistic effect in various human cancer cell lines (breast, ovarian, colon, prostate), independently of the p53 status. Detailed molecular analysis showed that the combination caused cancer cells to undergo premature mitosis before the end of DNA replication, with damaged DNA leading to cell death partly by apoptosis. In vivo treatment of mice bearing OVCAR-5 xenografts with the combination of Chk1 and Wee1 inhibitors led to greater tumor growth inhibition than with the inhibitors used as single agents with no toxicity. These data provide a strong rationale for the clinical investigation of the combination of a Chk1 and a Wee1 inhibitor.
Chk1 inhibitors for novel cancer treatment. [2019]Chemo- and radiotherapies that target DNA are the mainstay of cancer treatment. In response to DNA damage, cells are arrested in multiple checkpoints in the cell cycle to allow the damaged DNA to be repaired before progressing into mitosis. Normal cells are arrested in the G1 phase mediated by the p53 tumor suppressor, and p53-deficient cancer cells are arrested in the S or G2 phase. Checkpoint kinase 1 (Chk 1) is a serine / threonine protein kinase and a key mediator in the DNA damage-induced checkpoint network. When the G2 or S checkpoint is abrogated by the inhibition of Chk1, p53-deficient cancer cells undergo mitotic catastrophe and eventually apoptosis, whereas normal cells are still arrested in the G1 phase. Thus, Chk1 inhibitors can preferentially potentiate the efficacy of DNA damaging agents in cancer cells, and Chk1 is an attractive therapeutic target for cancer treatment, especially since approximately 50% of all human cancers are p53-deficient. This review discusses the rationale of Chk1 as an anticancer target, the structural basis for designing Chk1 inhibitors, and recently disclosed Chk1 inhibitors.
Assessment of chk1 phosphorylation as a pharmacodynamic biomarker of chk1 inhibition. [2022]Chk1 inhibitors, such as AZD7762, are in clinical development in combination with cytotoxic agents for the treatment of solid tumors, including pancreatic cancers. To maximize the likelihood of their clinical success, it is essential to optimize drug scheduling as well as pharmacodynamic biomarkers in preclinical models.
mTORC1 and DNA-PKcs as novel molecular determinants of sensitivity to Chk1 inhibition. [2021]Chk1 inhibitors are currently under clinical evaluation as single agents and in combination with cytotoxic chemotherapy. Understanding determinants of sensitivity and novel combinations is critical for further clinical development.
CHEK again: revisiting the development of CHK1 inhibitors for cancer therapy. [2016]CHEK1 encodes the serine/threonine kinase CHK1, a central component of the DNA damage response. CHK1 regulates cell cycle checkpoints following genotoxic stress to prevent the entry of cells with damaged DNA into mitosis and coordinates various aspects of DNA repair. Accordingly, CHK1 has become a target of considerable interest in oncology. CHK1 inhibitors potentiate the efficacy of DNA-damaging chemotherapeutics by abrogating CHK1-mediated cell cycle arrest and preventing repair of damaged DNA. In addition, CHK1 inhibitors interfere with the biological role of CHK1 as a principal regulator of the cell cycle that controls the initiation of DNA replication, stabilizes replication forks, and coordinates mitosis. Since these functions of CHK1 facilitate progression through an unperturbed cell cycle, CHK1 inhibitors are being developed not only as chemopotentiators, but also as single-agent therapies. This review is intended to provide information on the current progress of CHK1 inhibitors in pre-clinical and clinical development and will focus on mechanisms of single-agent activity and potential strategies for patient tailoring and combinations with non-genotoxic agents.
Design, Synthesis, and Biological Evaluation of Orally Bioavailable CHK1 Inhibitors Active against Acute Myeloid Leukemia. [2021]Checkpoint kinase 1 (CHK1) is a central component in DNA damage response and has emerged as a target for antitumor therapeutics. Herein, we describe the design, synthesis, and biological evaluation of a novel series of potent diaminopyrimidine CHK1 inhibitors. The compounds exhibited moderate to potent CHK1 inhibition and could suppress the proliferation of malignant hematological cell lines. The optimized compound 13 had a CHK1 IC50 value of 7.73±0.74 nM, and MV-4-11 cells were sensitive to it (IC50 =0.035±0.007 μM). Furthermore, compound 13 was metabolically stable in mouse liver microsomes in vitro and displayed moderate oral bioavailability in vivo. Moreover, treatment of MV-4-11 cells with compound 13 for 2 h led to robust inhibition of CHK1 autophosphorylation on serine 296. Based on these biochemical results, we consider compound 13 to be a promising CHK1 inhibitor and potential anticancer therapeutic agent.
Design of Novel Chemotherapeutic Agents Targeting Checkpoint Kinase 1 Using 3D-QSAR Modeling and Molecular Docking Methods. [2019]Checkpoint kinase 1 (Chk1) has emerged as a potential therapeutic target for design and development of novel anticancer drugs.