BBI-825 for Solid Tumors

(STARMAP Trial)

Recruiting at 4 trial locations

Overseen By Jaye Meyer

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Boundless Bio

Must not be taking: CYP3A inhibitors

Disqualifiers: Hematologic malignancies, CNS malignancy, HIV, others

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

Compensation: Varies

Number of Visits: Unknown

42 Participants Needed

Trial Summary

What is the purpose of this trial?

BBI-825 is a potent, selective, oral, small molecule inhibitor of ribonucleotide reductase (RNR). This is a first-in-human, open-label, non-randomized, 3-part, Phase 1/2 study to determine the safety profile and identify the maximum tolerated dose and recommended Phase 2 dose of BBI-825 administered as a single agent and in combination with select targeted therapies.

Do I need to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop all current medications, but you cannot use strong inhibitors or inducers of CYP3A, CYP2C8, CYP2C9, or CYP2C19. Also, you must not have taken any standard anticancer drugs within 4 weeks or 5 half-lives before the trial.

Will I have to stop taking my current medications?

The trial requires that you stop taking any approved or standard anticancer drugs or biological products at least 4 weeks before starting. Also, you cannot use strong inhibitors or inducers of certain enzymes (CYP3A, CYP2C8, CYP2C9, or CYP2C19) while participating.

What data supports the idea that BBI-825 for Solid Tumors is an effective treatment?

The available research shows that immune checkpoint inhibitors (ICIs), a type of treatment similar to BBI-825, have been effective in treating triple-negative breast cancer (TNBC), a type of solid tumor. Studies have shown that ICIs can improve survival rates and control the disease better when combined with chemotherapy. For example, the KEYNOTE-355 study found that combining ICIs with chemotherapy improved survival for patients with certain types of TNBC. Although specific data on BBI-825 is not provided, the success of similar treatments suggests that BBI-825 could also be effective for solid tumors. ^{1 2 3 4 5}

What safety data is available for BBI-825 in treating solid tumors?

The provided research does not specifically mention BBI-825 or its safety data. However, it discusses the safety concerns of Bruton's tyrosine kinase inhibitors (BTKis), which include cardiovascular side effects such as atrial fibrillation and potential cardiac risks. Additionally, there is a risk of hepatitis B virus reactivation in patients with certain lymphomas using BTKis. These findings may be relevant if BBI-825 is a BTKi. ^{6 7 8 9 10}

What safety information is available for BBI-825 in humans?

Bruton's tyrosine kinase inhibitors, which may include BBI-825, have been associated with cardiovascular side effects like atrial fibrillation (irregular heartbeat) and potential reactivation of hepatitis B virus (HBV) in some patients. ^{6 7 8 9 10}

Is the drug BBI-825 promising for treating solid tumors?

Yes, BBI-825, a type of BTK inhibitor, shows promise for treating solid tumors. BTK inhibitors have been repurposed to help patients with chemotherapy-resistant cancers, and they can enhance the effectiveness of other cancer treatments. They also help the immune system fight cancer better, which can lead to reduced tumor growth and improved treatment responses. ^{6 11 12 13 14}

How is the drug BBI-825 different from other treatments for solid tumors?

BBI-825 is unique because it is a Bruton's tyrosine kinase (BTK) inhibitor, which is being repurposed for solid tumors, offering potential benefits for patients who are resistant to chemotherapy. BTK inhibitors like BBI-825 may help overcome resistance to other treatments and enhance the effectiveness of immunotherapies by reducing immune suppression in the tumor environment. ^{6 11 12 13 14}

Research Team

Klaus Wagner, MD

Principal Investigator

Boundless Bio

Eligibility Criteria

This trial is for individuals with solid tumors that have developed resistance to other treatments. Participants must have specific gene amplifications linked to this resistance. The study excludes those who don't meet the necessary health standards or might be at risk due to the treatment.

Inclusion Criteria

Availability of FFPE tumor tissue, archival or newly obtained

My liver and kidney functions are normal.

My cancer has spread, can't be surgically removed, and hasn't responded to standard treatments.

Exclusion Criteria

I have not been treated with specific RNR inhibitor drugs before.

I haven't taken any cancer drugs or biological products in the last 4 weeks.

I have or had lung inflammation that needed strong medication.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Single agent BBI-825 is administered orally twice daily in 28-day cycles to determine the maximum tolerated dose and recommended Phase 2 dose

28 days per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of treatment emergent adverse events

30 days

Treatment Details

Interventions

• BBI-825

Trial Overview The trial is testing BBI-825, a new oral medication aimed at stopping tumor growth by inhibiting an enzyme called RNR. It's given alone or with other targeted therapies, and researchers are looking for the safest and most effective dose.

Participant Groups

Group I: Single Agent Dose Escalation Experimental Treatment 1 Intervention

Single agent BBI-825, administered orally, twice daily, in 28-day cycles

Who Is Running the Clinical Trial?

Boundless Bio

Lead Sponsor

Trials

2

Recruited

190+

Findings from Research

Immune checkpoint inhibitors (ICIs) have shown promising efficacy in treating triple-negative breast cancer (TNBC), particularly in patients with high PD-L1 expression, leading to improved survival rates when combined with chemotherapy.

Recent trials, such as KEYNOTE-355 and KEYNOTE-522, demonstrated that adding ICIs to standard chemotherapy not only enhances progression-free survival in metastatic TNBC but also increases pathologic complete response rates in early-stage disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of Immunotherapy in Breast Cancer. Jacob, SL., Huppert, LA., Rugo, HS.[2023]

Immune checkpoint inhibitors (ICIs) show promise for treating brain metastases in triple-negative breast cancer (TNBC), but only a small fraction (3.3%) of patients in clinical trials for ICIs had brain metastases, highlighting a significant gap in research.

There is a critical need for more inclusive clinical trials and real-world studies to evaluate the safety and efficacy of ICIs specifically for patients with breast cancer brain metastases, as current data is limited and does not adequately address this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune Checkpoint Inhibitors in the Treatment of Breast Cancer Brain Metastases. Schlam, I., Gatti-Mays, ME.[2022]

Next-generation immunotherapies (NGIO) targeting various immune checkpoints and costimulatory molecules have shown promise in early clinical trials for treating triple negative breast cancer (TNBC), demonstrating safety and early signs of antitumor activity.

To maximize the effectiveness of these therapies, patient selection based on immune biomarkers will be crucial, allowing for tailored treatment strategies that consider individual patient and tumor characteristics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Investigational immunomodulatory drugs for enhancement of triple negative breast cancer (TNBC) immunotherapy: early phase development. Tarantino, P., Antonarelli, G., Ascione, L., et al.[2022]

Immune checkpoint inhibitors (ICIs) have emerged as a promising treatment for advanced triple-negative breast cancer (TNBC), particularly for patients with PD-L1-positive tumors, leading to improved clinical outcomes and long-term disease control in some cases.

In early-stage TNBC, ICI-based combination therapies show potential benefits regardless of PD-L1 expression, indicating that immunotherapy could be effective even in patients who do not typically express this marker.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The evolving role of immune checkpoint inhibitors in the treatment of triple-negative breast cancer. Steiner, M., Tan, AR.[2021]

Immune checkpoint inhibitors (ICIs) show promise as a treatment for a small group of patients with metastatic triple negative breast cancer (mTNBC), indicating potential for immunotherapy in this challenging cancer type.

Combination therapies involving ICIs, such as chemoimmunotherapy for PD-L1 positive patients, have demonstrated significant efficacy and are being actively researched to improve treatment outcomes for mTNBC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune-based combinations for metastatic triple negative breast cancer in clinical trials: current knowledge and therapeutic prospects. Rizzo, A., Ricci, AD., Lanotte, L., et al.[2022]

Bruton's tyrosine kinase (BTK) inhibitors, already approved by the FDA, show promise as new treatments for patients with solid tumors that are resistant to traditional chemotherapy.

Emerging evidence suggests that BTK inhibitors could be combined with other therapies to create effective treatment regimens for metastatic and therapy-refractory solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting Solid Tumors With BTK Inhibitors. Uckun, FM., Venkatachalam, T.[2021]

Bruton's tyrosine kinase inhibitors (BTKis) are effective in treating B-cell malignancies but are associated with cardiovascular side effects, particularly an increased risk of atrial fibrillation, bleeding, and hypertension.

Newer generations of BTKis may have a lower risk of cardiovascular issues, but long-term safety data is still lacking, highlighting the need for careful management of cardiovascular risk factors in patients undergoing BTKi treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diagnosis and Management of Cardiovascular Effects of Bruton's Tyrosine Kinase Inhibitors. Aghel, N., Baro Vila, RC., Lui, M., et al.[2023]

Icotinib hydrochloride, a selective EGFR TKI, was found to be generally well tolerated in 36 patients with advanced solid tumors, particularly non-small-cell lung cancer (NSCLC), with manageable side effects like rash and diarrhea.

The study showed promising clinical activity, with 7 out of 33 NSCLC patients achieving a partial response and 7 showing stable disease, suggesting that icotinib could be an effective treatment option after platinum-based chemotherapy failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of icotinib hydrochloride (BPI-2009H), an oral EGFR tyrosine kinase inhibitor, in patients with advanced NSCLC and other solid tumors. Zhao, Q., Shentu, J., Xu, N., et al.[2022]

In a study of 55 patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) receiving BTK inhibitors, 7.69% of those with resolved HBV infection experienced hepatitis B virus reactivation (HBVr), indicating a moderate risk during treatment.

The overall response rate to BTK inhibitors was 70.9%, and the presence of HBV infection did not impact treatment efficacy, suggesting that while monitoring for HBVr is important, BTK inhibitors remain effective regardless of HBV status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk of HBV reactivation in relapsed or refractory diffuse large B-cell lymphoma patients receiving Bruton tyrosine kinase inhibitors therapy. Ni, Y., Gao, L., Lu, Y., et al.[2022]

A study analyzing 10,320 cardiac event reports linked to Bruton tyrosine kinase inhibitors (BTKIs) found that 17.63% of these cases involved death or life-threatening events, indicating significant cardiac risks associated with these medications.

Ibrutinib was identified as having the strongest association with cardiac complications, particularly atrial fibrillation, while acalabrutinib showed a statistically lower risk compared to ibrutinib, highlighting the variability in cardiotoxicity among different BTKIs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacovigilance analysis of cardiac risks associated with Bruton tyrosine kinase inhibitors. Zhai, Y., Hu, F., Shi, W., et al.[2023]

In a study using immunocompromised mice with TCF3-PBX1 positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL), treatment with the BTK inhibitor ibrutinib did not extend the lifespan of the mice compared to those receiving a placebo, indicating limited efficacy in this context.

While ibrutinib was shown to be biologically active by reducing phospho-BTK levels, it did not improve leukemic cell viability or tumor growth, and it exhibited an antagonistic effect when combined with vincristine, suggesting it may not be the best treatment option for this specific type of leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib is not an effective drug in primografts of TCF3-PBX1. van de Ven, C., Boeree, A., Stalpers, F., et al.[2021]

Ibrutinib, a BTK inhibitor, effectively reduces the immunosuppressive functions of myeloid-derived suppressor cells (MDSCs) in neuroblastoma (NB) models, leading to increased CD8+ T cell infiltration and decreased tumor growth.

The study shows that using ibrutinib in combination with anti-PDL1 checkpoint inhibitors enhances the antitumor immune response, suggesting a promising strategy for improving immunotherapy outcomes in solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BTK Inhibition Reverses MDSC-Mediated Immunosuppression and Enhances Response to Anti-PDL1 Therapy in Neuroblastoma. Ishfaq, M., Pham, T., Beaman, C., et al.[2023]

In a study involving 122 patients with advanced solid tumors, the combination of ibrutinib and durvalumab showed an acceptable safety profile, with adverse events consistent with known effects of both drugs.

However, the antitumor activity was limited, with overall response rates of only 2% for pancreatic cancer, 3% for breast cancer, and 0% for non-small cell lung cancer, indicating that this combination may not be effective for these types of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase 1b/2 Study of the Bruton Tyrosine Kinase Inhibitor Ibrutinib and the PD-L1 Inhibitor Durvalumab in Patients with Pretreated Solid Tumors. Hong, D., Rasco, D., Veeder, M., et al.[2021]

High expression of Bruton's tyrosine kinase (BTK) in non-small-cell lung carcinoma (NSCLC) patients is associated with poor prognosis and resistance to EGFR tyrosine kinase inhibitors (TKIs), based on analysis of surgical specimens from 80 patients.

In laboratory studies, inhibiting BTK with Acalabrutinib enhanced the effectiveness of EGFR TKIs like Gefitinib and Osimertinib, suggesting that targeting BTK could be a promising strategy to overcome TKI resistance in NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bruton's tyrosine kinase (BTK) mediates resistance to EGFR inhibition in non-small-cell lung carcinoma. Yeh, CT., Chen, TT., Satriyo, PB., et al.[2021]

References

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

Role of Immunotherapy in Breast Cancer. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Immune Checkpoint Inhibitors in the Treatment of Breast Cancer Brain Metastases. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Investigational immunomodulatory drugs for enhancement of triple negative breast cancer (TNBC) immunotherapy: early phase development. [2022]

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

The evolving role of immune checkpoint inhibitors in the treatment of triple-negative breast cancer. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Immune-based combinations for metastatic triple negative breast cancer in clinical trials: current knowledge and therapeutic prospects. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Targeting Solid Tumors With BTK Inhibitors. [2021]

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

Diagnosis and Management of Cardiovascular Effects of Bruton's Tyrosine Kinase Inhibitors. [2023]

8. Ireland pubmed.ncbi.nlm.nih.gov

Phase I study of icotinib hydrochloride (BPI-2009H), an oral EGFR tyrosine kinase inhibitor, in patients with advanced NSCLC and other solid tumors. [2022]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Risk of HBV reactivation in relapsed or refractory diffuse large B-cell lymphoma patients receiving Bruton tyrosine kinase inhibitors therapy. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Pharmacovigilance analysis of cardiac risks associated with Bruton tyrosine kinase inhibitors. [2023]

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

Ibrutinib is not an effective drug in primografts of TCF3-PBX1. [2021]

12. Switzerland pubmed.ncbi.nlm.nih.gov

BTK Inhibition Reverses MDSC-Mediated Immunosuppression and Enhances Response to Anti-PDL1 Therapy in Neuroblastoma. [2023]

13. Switzerland pubmed.ncbi.nlm.nih.gov

A Phase 1b/2 Study of the Bruton Tyrosine Kinase Inhibitor Ibrutinib and the PD-L1 Inhibitor Durvalumab in Patients with Pretreated Solid Tumors. [2021]

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

Bruton's tyrosine kinase (BTK) mediates resistance to EGFR inhibition in non-small-cell lung carcinoma. [2021]