BSB-1001 for Blood Cancers

Recruiting at 4 trial locations

Overseen By Study Director: Erkut Bahceci, MD, BlueSphere Bio

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: BlueSphere Bio, Inc

Must not be taking: Investigational agents, Checkpoint inhibitors

Disqualifiers: Weight > 100 kg, Other malignancy, Infections, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 1 day

38 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this clinical trial is to test BSB-1001 which is a new type of cellular therapy to treat blood cancers (AML, ALL and MDS). It will evaluate the safety of BSB-1001 and also determine whether it works to prevent relapse of your cancer.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it mentions that you cannot have had certain treatments like CAR-T therapy within 2 years or investigational agents recently, so it's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug BSB-1001 for blood cancers?

Research on similar treatments, like BH3-mimetics, shows they can effectively target and kill cancer cells in blood cancers by overcoming blocks in apoptosis (a process of programmed cell death). This suggests that BSB-1001, if it works similarly, might also be effective in treating blood cancers. ^{1 2 3 4 5}

Is BSB-1001 safe for humans?

Dasatinib, which may be related to BSB-1001, has been studied for safety in various blood cancers. In a study with patients having acute lymphoblastic leukemia, dasatinib was generally well-tolerated, with most side effects being mild and manageable. Another study in myelodysplastic syndrome patients also found dasatinib to be safe, though its effectiveness was limited. ^{6 7 8 9 10}

How does the drug BSB-1001 differ from other treatments for blood cancers?

BSB-1001 is unique because it may act as a BH3 mimetic, similar to the small-molecule S1, which inhibits multiple anti-apoptotic proteins like Bcl-2, Mcl-1, and Bcl-XL that are often overexpressed in blood cancers. This multi-targeted approach could potentially make it more effective in inducing cancer cell death compared to treatments that target only one of these proteins. ^{1 11 12 13 14}

Eligibility Criteria

This trial is for patients with blood cancers like AML, ALL, or MDS who are getting a stem cell transplant from a donor that matches their tissue type. Participants should not have had previous treatments that would interfere with the study.

Inclusion Criteria

I have a high-risk blood cancer such as AML, ALL, or MDS.

Suitable for one of the approved conditioning regimens as defined in the protocol

I have a donor match for my transplant who is fully compatible.

Exclusion Criteria

My organs are not functioning well enough for the study.

I have had a stem cell transplant before.

I haven't had CAR-T therapy in the last 2 years, unless it was for ALL with an autologous product.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning

Patients undergo myeloablative conditioning regimens including fludarabine, thiotepa, total body irradiation, or busulfan, melphalan, fludarabine

1-2 weeks

Treatment

Patients receive CD34-selected alloHSCT followed by BSB-1001 on day 0 without prophylactic immunosuppression

1 day

Follow-up

Participants are monitored for safety and effectiveness, including cellular kinetics of BSB-1001 and incidence of GVHD

365 days

Expansion Cohort (optional)

Additional AML patients may be enrolled at the recommended dose level if the maximum tolerated dose is reached

Treatment Details

Interventions

• BSB-1001

Trial Overview The study tests BSB-1001, an experimental cellular therapy added to standard care (SOC), in two parts: first, finding the right dose and then seeing how well it works at preventing cancer relapse after stem cell transplants.

Participant Groups

Group I: Dose Escalation Cohorts Experimental Treatment 1 Intervention

AML, ALL and MDS HLA-A\*02:01 and HA-1-positive (H/H or H/R) patients with an identified HLA-matched, HA-1-negative (R/R) donor will be dosed in dose escalation cohorts

Group II: BSB-1001 Expansion Dose Experimental Treatment 1 Intervention

Once the maximum tolerated dose (MTD) or promising dose is reached additional AML HLA-A\*02:01 and HA-1-positive (H/H or H/R) patients with an identified HLA-matched, HA-1-negative (R/R) donor will be enrolled in the expansion cohort.

Who Is Running the Clinical Trial?

BlueSphere Bio, Inc

Lead Sponsor

Trials

1

Recruited

40+

Findings from Research

The small-molecule S1, a BH3 mimetic that inhibits Bcl-2, Mcl-1, and Bcl-XL, showed variable sensitivity in killing leukaemic cells, with lethal dose 50 (LD(50)) values differing significantly across five leukaemic cell lines and 41 newly diagnosed leukaemia samples.

A predictive index for S1's effectiveness was established, indicating that the ratio of phosphorylated Bcl-2 to total Bcl-2 and Mcl-1 can forecast the response to treatment, revealing a novel mechanism where phosphorylated Bcl-2 sequesters pro-apoptotic proteins, preventing their activation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An antiapoptotic Bcl-2 family protein index predicts the response of leukaemic cells to the pan-Bcl-2 inhibitor S1. Zhang, Z., Liu, Y., Song, T., et al.[2021]

BH3-mimetics are a new class of drugs that can directly target and reverse the mechanisms that allow tumors to evade apoptosis, which is crucial for tumor survival and resistance to treatment.

Clinical trials have shown that BH3-mimetics have significant anti-tumor activity in certain blood cancers and may enhance the effectiveness of other cancer therapies across a wider range of malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overcoming blocks in apoptosis with BH3-mimetic therapy in haematological malignancies. Khaw, SL., Huang, DC., Roberts, AW.[2021]

In a study of 57 patients with newly diagnosed B cell-derived hematologic malignancies, the level of B cell lymphocyte stimulating factor (BLyS) was found to be significantly higher compared to healthy volunteers, indicating its potential role as a biomarker for these diseases.

After chemotherapy, BLyS levels significantly decreased, suggesting that monitoring BLyS levels could help assess treatment response and guide diagnosis and staging in patients with B cell-derived malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Abnormal Expression and Clinical Significance of B Lymphocyte Stimulating Factor in B Cell-derived Malignant Hematologic Diseases]. Han, XL., Zhang, XY., Li, JD., et al.[2018]

A study of over 100 hematological cell line models revealed that certain mantle cell lymphoma (MCL) cell lines are highly sensitive to B cell receptor (BCR) signaling inhibitors like ibrutinib and sotrastaurin, linked to chronic activation of the classical NF-κB pathway.

In contrast, MCL cell lines that are insensitive to these inhibitors often have genetic mutations affecting the alternative NF-κB pathway, suggesting that targeting the protein kinase NIK could be a promising new treatment strategy for patients with refractory MCL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacological and genomic profiling identifies NF-κB-targeted treatment strategies for mantle cell lymphoma. Rahal, R., Frick, M., Romero, R., et al.[2023]

BB-10010, a variant of MIP-1alpha, was well-tolerated in a phase II study involving 30 breast cancer patients undergoing chemotherapy, showing no severe adverse events and a low incidence of febrile neutropenia (4%).

Patients receiving BB-10010 had significantly higher neutrophil levels after treatment compared to controls, with a notable fivefold increase in granulocyte/macrophage colony-forming cells, suggesting enhanced recovery of the bone marrow after chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized phase-II study of BB-10010 (macrophage inflammatory protein- 1alpha) in patients with advanced breast cancer receiving 5-fluorouracil, adriamycin, and cyclophosphamide chemotherapy. Clemons, MJ., Marshall, E., Dürig, J., et al.[2021]

In a phase 2 study involving 36 patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL), dasatinib demonstrated significant efficacy, achieving major hematologic responses in 42% of patients and complete cytogenetic responses in 58%.

Dasatinib was found to be tolerable, with only 6% of patients discontinuing treatment due to toxicity, and most adverse events were manageable, indicating it is a safe and effective option for patients with Ph-positive ALL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study. Ottmann, O., Dombret, H., Martinelli, G., et al.[2022]

In a study of primary large B-cell lymphoma (DLBCL), 38% of tumors expressed active Src family kinases, which are potential targets for the drug dasatinib, and this expression was linked to poorer prognostic indicators.

Sensitivity to dasatinib varied significantly among DLBCL cell lines, with resistance associated with specific signaling changes that prevented effective inhibition of BCR-mediated pathways, highlighting the complexity of treatment responses in DLBCL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic implications of Src independent calcium mobilization in diffuse large B-cell lymphoma. Hollmann, CA., Tzankov, A., Martínez-Marignac, VL., et al.[2015]

In a phase II study involving 18 patients with higher-risk myelodysplastic syndrome and related conditions, dasatinib (100 mg/day) showed limited efficacy, with only 3 patients responding positively and 10 experiencing disease progression.

The treatment was found to be safe, with toxicities consistent with previous reports, indicating that while dasatinib may not be highly effective for this patient group, it does not pose significant safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II pilot study of oral dasatinib in patients with higher-risk myelodysplastic syndrome (MDS) who failed conventional therapy. Duong, VH., Jaglal, MV., Zhang, L., et al.[2015]

SAR103168, a novel multi-targeted kinase inhibitor, was tested in a phase I trial involving 29 patients aged 18-83 with relapsed/refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

The treatment showed a pharmacokinetic profile with expected adverse events for the patient population, and no specific toxicities related to SAR103168 were identified, although the study was discontinued before reaching the maximum tolerated dose due to unpredictable drug exposure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of SAR103168, a novel multi-kinase inhibitor, in patients with refractory/relapsed acute leukemia or high-risk myelodysplastic syndrome. Roboz, GJ., Khoury, HJ., Jabbour, E., et al.[2021]

Ibrutinib, an oral BTK inhibitor, has shown durable clinical responses in patients with chronic lymphocytic leukemia (CLL), including those with high-risk genetic abnormalities, and is also effective in mantle cell lymphoma (MCL) and Waldenström's macroglobulinemia (WM).

While generally well tolerated, ibrutinib can cause specific side effects like bleeding and atrial fibrillation, particularly in older patients, and ongoing studies are exploring its use in combination with other therapies to enhance efficacy and reduce toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current Status of Bruton's Tyrosine Kinase Inhibitor Development and Use in B-Cell Malignancies. Aw, A., Brown, JR.[2021]

BS-HH-002, a modified version of homoharringtonine, shows strong antitumor activity against pancreatic cancer by completely degrading the anti-apoptosis protein MCL-1, leading to inhibited cell growth and increased cell death.

In animal studies, BS-HH-002 demonstrated a faster absorption into the bloodstream and significantly less heart toxicity compared to its predecessor, HHT, suggesting it may be a safer and more effective treatment option for solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic effects of an innovative BS-HH-002 drug on pancreatic cancer cells via induction of complete MCL-1 degradation. Wang, AM., Qiu, R., Zhang, D., et al.[2023]

The BNT162b2 vaccine significantly increases both antibody and T-cell responses in patients with hematological malignancies, indicating a positive immunogenic effect after two doses.

However, only 47% of these patients achieved a protective antibody level, compared to 87% of healthy controls, highlighting that many patients may not develop sufficient immunity against COVID-19 after vaccination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Weak immunogenicity of SARS-CoV-2 vaccine in patients with hematologic malignancies. Malard, F., Gaugler, B., Gozlan, J., et al.[2021]

The novel Hsp90 inhibitor BJ-B11 demonstrated significant antitumor activity against human chronic myeloid leukemia K562 cells, with an IC(50) of 1.1 μM after 48 hours, indicating effective growth inhibition with minimal toxicity to normal cells.

BJ-B11 induces apoptosis through mechanisms including cell cycle arrest, degradation of key proteins like Bcr-Abl and Akt, and activation of caspases, suggesting it could be a promising treatment for chronic myeloid leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BJ-B11, a novel Hsp90 inhibitor, induces apoptosis in human chronic myeloid leukemia K562 cells through the mitochondria-dependent pathway. Ju, HQ., Wang, SX., Xiang, YF., et al.[2016]

Novobiocin (NB) effectively inhibits the growth of Bcr-Abl-positive leukemia cells, such as HL-60/Bcr-Abl and K562, by inducing apoptosis through the activation of caspases and the accumulation of cytochrome c.

NB disrupts the interaction between Bcr-Abl and Hsp90, leading to decreased levels of Bcr-Abl protein and promoting its degradation, making it a potential treatment option even for imatinib-resistant leukemia cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Disruption of the Bcr-Abl/Hsp90 protein complex: a possible mechanism to inhibit Bcr-Abl-positive human leukemic blasts by novobiocin. Wu, LX., Xu, JH., Zhang, KZ., et al.[2015]

References

1. England pubmed.ncbi.nlm.nih.gov

An antiapoptotic Bcl-2 family protein index predicts the response of leukaemic cells to the pan-Bcl-2 inhibitor S1. [2021]

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

Overcoming blocks in apoptosis with BH3-mimetic therapy in haematological malignancies. [2021]

3. China pubmed.ncbi.nlm.nih.gov

[Abnormal Expression and Clinical Significance of B Lymphocyte Stimulating Factor in B Cell-derived Malignant Hematologic Diseases]. [2018]

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

Pharmacological and genomic profiling identifies NF-κB-targeted treatment strategies for mantle cell lymphoma. [2023]

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

A randomized phase-II study of BB-10010 (macrophage inflammatory protein- 1alpha) in patients with advanced breast cancer receiving 5-fluorouracil, adriamycin, and cyclophosphamide chemotherapy. [2021]

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

Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Therapeutic implications of Src independent calcium mobilization in diffuse large B-cell lymphoma. [2015]

8. England pubmed.ncbi.nlm.nih.gov

Phase II pilot study of oral dasatinib in patients with higher-risk myelodysplastic syndrome (MDS) who failed conventional therapy. [2015]

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

Phase I trial of SAR103168, a novel multi-kinase inhibitor, in patients with refractory/relapsed acute leukemia or high-risk myelodysplastic syndrome. [2021]

10. New Zealand pubmed.ncbi.nlm.nih.gov

Current Status of Bruton's Tyrosine Kinase Inhibitor Development and Use in B-Cell Malignancies. [2021]

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

Therapeutic effects of an innovative BS-HH-002 drug on pancreatic cancer cells via induction of complete MCL-1 degradation. [2023]

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

Weak immunogenicity of SARS-CoV-2 vaccine in patients with hematologic malignancies. [2021]

13. Netherlands pubmed.ncbi.nlm.nih.gov

BJ-B11, a novel Hsp90 inhibitor, induces apoptosis in human chronic myeloid leukemia K562 cells through the mitochondria-dependent pathway. [2016]

14. England pubmed.ncbi.nlm.nih.gov

Disruption of the Bcr-Abl/Hsp90 protein complex: a possible mechanism to inhibit Bcr-Abl-positive human leukemic blasts by novobiocin. [2015]