CHK1 Inhibitor for Lung Cancer

(POTENTIATE Trial)

Recruiting at 15 trial locations

Overseen By Rebecca Reynolds

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Boundless Bio

Must not be taking: CHK1 inhibitors, EGFR inhibitors, FGFR inhibitors

Disqualifiers: Hematologic malignancies, CNS malignancy, HBV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

150 Participants Needed

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. ^{1 2 3 4 5}

What 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. ^{4 5 6 7 8}

Research Team

Klaus Wagner, MD, PhD

Principal Investigator

Boundless Bio

Eligibility 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.

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

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

Treatment Details

Interventions

• BBI-355

Trial Overview 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.

Participant Groups

Group I: Single Agent Dose Expansion Experimental Treatment 1 Intervention

Single agent BBI-355, administered orally in 28-day cycles

Group II: Single Agent Dose Escalation Experimental Treatment 1 Intervention

Single agent BBI-355, administered orally in 28-day cycles

Group III: Dose Escalation in Combination with FGFR Inhibitor Experimental Treatment 2 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 Inhibitor Experimental Treatment 2 Interventions

Combination therapy of BBI-355 and EGFR inhibitor erlotinib, administered orally in 28-day cycles.

Who Is Running the Clinical Trial?

Boundless Bio

Lead Sponsor

Trials

2

Recruited

190+

Findings from Research

CCT244747 is the first orally bioavailable Chk1 inhibitor that enhances the effectiveness of radiation therapy in bladder and head and neck cancer cell lines, showing promising results in both in vitro and in vivo models.

The mechanism of action involves disrupting the radiation-induced G2 cell cycle arrest, allowing cancer cells to enter mitosis prematurely, which contributes to its radiosensitizing effects and potential clinical application.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An orally bioavailable Chk1 inhibitor, CCT244747, sensitizes bladder and head and neck cancer cell lines to radiation. Patel, R., Barker, HE., Kyula, J., et al.[2022]

Targeting Chk1 protein kinase with inhibitors can significantly enhance the effectiveness of cancer treatments, especially when combined with Wee1 inhibitors, as shown in various human cancer cell lines including breast and ovarian cancers.

In vivo studies in mice demonstrated that the combination of Chk1 and Wee1 inhibitors led to greater tumor growth inhibition compared to using either inhibitor alone, without causing toxicity, suggesting a promising new treatment strategy for certain cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined inhibition of Chk1 and Wee1: in vitro synergistic effect translates to tumor growth inhibition in vivo. Carrassa, L., Chilà, R., Lupi, M., et al.[2020]

Chk1 inhibitors can selectively enhance the effectiveness of DNA-damaging cancer treatments by causing p53-deficient cancer cells to undergo mitotic catastrophe and apoptosis, while normal cells remain unaffected due to their G1 phase arrest.

Since about 50% of human cancers lack functional p53, targeting Chk1 presents a promising strategy for developing new cancer therapies that specifically exploit the vulnerabilities of these cancer cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chk1 inhibitors for novel cancer treatment. Tao, ZF., Lin, NH.[2019]

The combination of the Chk1 inhibitor AZD7762 with the chemotherapy drug gemcitabine significantly enhances the effectiveness of treatment against pancreatic cancer cells, particularly when AZD7762 is administered during or after gemcitabine.

The biomarker pS345 Chk1 was consistently elevated in response to the treatment, indicating that DNA damage plays a key role in the mechanism of action for this combination therapy, supporting further clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of chk1 phosphorylation as a pharmacodynamic biomarker of chk1 inhibition. Parsels, LA., Qian, Y., Tanska, DM., et al.[2022]

The Chk1 inhibitor V158411 enhances the effectiveness of mTOR inhibitors in p53 mutant colon cancer cells, leading to increased cell death and DNA damage, which suggests a promising combination therapy for this cancer type.

Downregulation of DNA repair proteins by mTOR inhibitors increases sensitivity to Chk1 inhibitors, and high levels of DNA-PKcs may serve as a biomarker to identify patients who could benefit from this combined treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

mTORC1 and DNA-PKcs as novel molecular determinants of sensitivity to Chk1 inhibition. Massey, AJ., Stephens, P., Rawlinson, R., et al.[2021]

CHK1 inhibitors are promising in cancer treatment as they enhance the effectiveness of DNA-damaging chemotherapy by blocking CHK1's role in cell cycle arrest and DNA repair, allowing cancer cells to be more susceptible to treatment.

These inhibitors are not only being explored as enhancers of existing therapies but also as standalone treatments, targeting CHK1's critical functions in regulating the cell cycle and DNA replication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CHEK again: revisiting the development of CHK1 inhibitors for cancer therapy. McNeely, S., Beckmann, R., Bence Lin, AK.[2016]

A novel CHK1 inhibitor, compound 13, demonstrated strong potency with an IC50 value of 7.73 nM and effectively suppressed the growth of malignant hematological cell lines, particularly MV-4-11 cells with an IC50 of 0.035 μM.

Compound 13 showed good metabolic stability in mouse liver microsomes and moderate oral bioavailability, indicating its potential as an effective and practical anticancer therapeutic agent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design, Synthesis, and Biological Evaluation of Orally Bioavailable CHK1 Inhibitors Active against Acute Myeloid Leukemia. Jin, T., Wang, P., Long, X., et al.[2021]

The study successfully developed reliable 3D-QSAR models for designing potent Chk1 inhibitors, with strong correlation coefficients indicating the models' predictive power based on a series of diazacarbazoles.

Molecular docking studies identified key interactions necessary for Chk1 inhibition, specifically hydrogen bonds with residues Lys38, Glu85, and Cys87, guiding the design of new inhibitors for potential experimental synthesis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design of Novel Chemotherapeutic Agents Targeting Checkpoint Kinase 1 Using 3D-QSAR Modeling and Molecular Docking Methods. Balupuri, A., Balasubramanian, PK., Cho, SJ.[2019]

References

1. Ireland pubmed.ncbi.nlm.nih.gov

An orally bioavailable Chk1 inhibitor, CCT244747, sensitizes bladder and head and neck cancer cell lines to radiation. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Combined inhibition of Chk1 and Wee1: in vitro synergistic effect translates to tumor growth inhibition in vivo. [2020]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Chk1 inhibitors for novel cancer treatment. [2019]

4. United States pubmed.ncbi.nlm.nih.gov

Assessment of chk1 phosphorylation as a pharmacodynamic biomarker of chk1 inhibition. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

mTORC1 and DNA-PKcs as novel molecular determinants of sensitivity to Chk1 inhibition. [2021]

6. England pubmed.ncbi.nlm.nih.gov

CHEK again: revisiting the development of CHK1 inhibitors for cancer therapy. [2016]

7. Germany pubmed.ncbi.nlm.nih.gov

Design, Synthesis, and Biological Evaluation of Orally Bioavailable CHK1 Inhibitors Active against Acute Myeloid Leukemia. [2021]

8. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Design of Novel Chemotherapeutic Agents Targeting Checkpoint Kinase 1 Using 3D-QSAR Modeling and Molecular Docking Methods. [2019]