ABL503 for Solid Cancers

Recruiting at 8 trial locations

Overseen By Juyeun Jeon

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: ABL Bio, Inc.

Must not be taking: Monoclonal antibodies, Steroids

Disqualifiers: Bowel obstruction, Pneumonitis, others

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

Compensation: Varies

Number of Visits: Unknown

100 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a new drug called ABL503 in patients with advanced cancers that have no other treatment options. It aims to find out if the drug is safe, how well patients can tolerate it, and if it shows any early signs of fighting cancer.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications before starting. You must not have had any anticancer monoclonal antibody treatment or investigational therapy within 28 days, chemotherapy or radiation therapy within 2 weeks, or targeted small molecule therapy within 5 half-lives before starting the study drug. Additionally, you should not be on systemic steroid therapy or any other immunosuppressive therapy within 14 days prior to the study drug administration.

What data supports the effectiveness of the drug ABL503 for solid cancers?

The research on MEDI5752, a similar type of drug that targets immune checkpoints, shows it is well tolerated and effective across different tumor types, suggesting that ABL503 might also be effective in treating solid cancers. ^{1 2 3 4 5}

What makes the drug ABL503 unique for treating solid cancers?

ABL503 is unique because it is a bispecific antibody that targets both LAG-3 and PD-L1, enhancing the immune system's ability to fight cancer by activating T cells more effectively than using separate treatments for each target. ^{6 7 8 9 10}

Eligibility Criteria

This trial is for adults with advanced solid tumors that have worsened after treatment or don't respond to standard therapies. Participants must have recovered from major side effects of previous treatments, except hair loss and certain stable conditions, and should have good blood, liver, and kidney function.

Inclusion Criteria

My side effects from previous treatments, except for hair loss or stable nerve damage, have mostly gone away.

My blood, liver, and kidney tests are all within normal ranges.

My cancer has returned or didn't respond to treatment and cannot be surgically removed.

Exclusion Criteria

I haven't had cancer antibody treatment or experimental therapy in the last 28 days.

I stopped previous immune therapy due to severe side effects needing steroids.

I haven't taken steroids or immunosuppressants in the last 14 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive ABL503 biweekly in a 28-day cycle to determine the maximum tolerated dose and recommended phase 2 dose

Up to 12 months

Biweekly visits

Dose Expansion

Participants receive ABL503 at the determined dose to further evaluate safety and preliminary antitumor activity

Up to 12 months

Biweekly visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• ABL503

Trial Overview ABL503 is being tested in this Phase 1 trial to find the safest dose for future studies. The study has three parts: finding the maximum tolerated dose (MTD), expanding the dose range (RP2D), and testing on specific tumor types.

Participant Groups

Group I: ABL503 Experimental Treatment 1 Intervention

ABL503 will be administered biweekly of every 28-day cycle in the dose-escalation. The dosing interval to be used in the dose-expansion part will be re-evaluated based on the emerging safety and PK data from the dose-escalation part of the study.

Who Is Running the Clinical Trial?

ABL Bio, Inc.

Lead Sponsor

Trials

6

Recruited

390+

Findings from Research

The maximum tolerated dose (MTD) of afatinib combined with paclitaxel was determined to be 40mg of afatinib with 80mg/m² of paclitaxel, showing manageable adverse effects such as diarrhea and fatigue in a study of 16 patients.

The combination treatment demonstrated promising antitumor activity, with 31% of patients achieving confirmed partial responses, particularly in non-small cell lung cancer, and half of the patients remaining on the study for at least 6 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of daily afatinib, an irreversible ErbB family blocker, in combination with weekly paclitaxel in patients with advanced solid tumours. Suder, A., Ang, JE., Kyle, F., et al.[2018]

The phase I trial of MEDI5752, a bispecific antibody that targets both PD-1 and CTLA4, shows that the drug is well tolerated by patients.

Preliminary results indicate that MEDI5752 is active in treating various tumor types, with durable responses observed, suggesting potential effectiveness in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MEDI5752 Suppresses Two Immune Checkpoints. [2022]

The combination of afatinib (40 mg QD) and vinorelbine (25 mg/m² weekly) was found to be tolerable in Japanese patients with advanced solid tumors, with dose modifications for adverse events allowing for better management of side effects.

Two patients experienced partial tumor responses, and eight had stable disease, indicating preliminary efficacy of this treatment regimen, which is recommended for further phase II/III trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of afatinib plus vinorelbine in Japanese patients with advanced solid tumors, including breast cancer. Mukai, H., Masuda, N., Ishiguro, H., et al.[2018]

In a pilot study involving 13 patients with advanced melanoma, breast cancer, and colon cancer, the drug PD-0325901 showed significant tolerability issues, particularly at doses of 15 mg twice daily or higher, leading to early termination of the study due to adverse effects like gait disturbance and memory impairment.

Despite the safety concerns, one patient achieved a complete response and five had stable disease, suggesting that PD-0325901 may have preliminary antitumor activity, warranting further investigation at lower doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pilot study of PD-0325901 in previously treated patients with advanced melanoma, breast cancer, and colon cancer. Boasberg, PD., Redfern, CH., Daniels, GA., et al.[2021]

In a meta-analysis of five studies involving 435 patients with stage IV EGFR-mutated non-small cell lung cancer, PD-L1-positive tumors were linked to significantly worse progression-free survival (PFS) outcomes compared to PD-L1-negative tumors, indicating that PD-L1 expression may negatively impact treatment effectiveness.

The analysis revealed that the negative impact of PD-L1 expression on PFS was more pronounced with older-generation EGFR tyrosine kinase inhibitors (TKIs) compared to third-generation TKIs, suggesting that the choice of treatment may influence outcomes based on PD-L1 status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of programmed death-ligand 1 expression on the patients of stage IV non-small cell lung cancer harboring epidermal growth factor receptor mutation: a systematic review and meta-analysis. Lee, CC., Soon, YY., Leong, CN., et al.[2022]

ABL501, a bispecific antibody targeting both LAG-3 and PD-L1, enhances T cell activation more effectively than using single antibodies, leading to improved immune responses against tumors.

In preclinical models, ABL501 demonstrated strong antitumor efficacy and is currently being evaluated in a first-in-human clinical trial, indicating its potential as a novel cancer immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

LAG-3xPD-L1 bispecific antibody potentiates antitumor responses of T cells through dendritic cell activation. Sung, E., Ko, M., Won, JY., et al.[2023]

In triple negative breast cancer (TNBC), which is particularly aggressive and has no targeted treatments, the protein geminin is overexpressed in about 50% of tumors, and its activity is regulated by the tyrosine kinase c-Abl, which is found in the nucleus of geminin-overexpressing tumors.

Inhibiting c-Abl with drugs like imatinib or nilotinib not only inactivates geminin but also converts it from promoting cancer to inducing cell death, showing promise as a novel treatment for aggressive breast cancers that overexpress geminin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Geminin overexpression promotes imatinib sensitive breast cancer: a novel treatment approach for aggressive breast cancers, including a subset of triple negative. Blanchard, Z., Mullins, N., Ellipeddi, P., et al.[2022]

ABL family kinases, while primarily known for their role in leukemia, are also implicated in various solid tumors where they promote processes like tumor growth, invasion, and metastasis through unique signaling pathways.

Targeting ABL kinases could potentially reduce tumor growth and prevent metastasis, but their dual role as both promoters and potential suppressors of tumors in different contexts highlights the need for careful consideration in treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

EnABLing Tumor Growth and Progression: Recent progress in unraveling the functions of ABL kinases in solid tumor cells. Tripathi, R., Liu, Z., Plattner, R.[2022]

The ABL tyrosine kinases, particularly ABL1 and ABL2, are implicated in the progression of various solid tumors, in addition to their established role in leukemia, based on findings from mouse models and genomic studies.

Preclinical studies indicate that small molecule inhibitors targeting ABL kinases may provide therapeutic benefits for certain solid tumors, suggesting a potential new treatment avenue for these cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Emerging Role of ABL Kinases in Solid Tumors. Wang, J., Pendergast, AM.[2022]

AP24534 is a new, potent oral multitargeted kinase inhibitor that effectively targets the BCR-ABL(T315I) mutation and other resistant BCR-ABL mutants in chronic myeloid leukemia (CML).

In preclinical studies, AP24534 not only inhibited tumor growth driven by the BCR-ABL(T315I) mutation in mice but also completely overcame resistance in laboratory tests, suggesting strong potential for clinical use in CML treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. O'Hare, T., Shakespeare, WC., Zhu, X., et al.[2023]

References

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

A phase I study of daily afatinib, an irreversible ErbB family blocker, in combination with weekly paclitaxel in patients with advanced solid tumours. [2018]

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

MEDI5752 Suppresses Two Immune Checkpoints. [2022]

3. Germany pubmed.ncbi.nlm.nih.gov

Phase I trial of afatinib plus vinorelbine in Japanese patients with advanced solid tumors, including breast cancer. [2018]

4. Germany pubmed.ncbi.nlm.nih.gov

Pilot study of PD-0325901 in previously treated patients with advanced melanoma, breast cancer, and colon cancer. [2021]

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

Impact of programmed death-ligand 1 expression on the patients of stage IV non-small cell lung cancer harboring epidermal growth factor receptor mutation: a systematic review and meta-analysis. [2022]

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

LAG-3xPD-L1 bispecific antibody potentiates antitumor responses of T cells through dendritic cell activation. [2023]

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

Geminin overexpression promotes imatinib sensitive breast cancer: a novel treatment approach for aggressive breast cancers, including a subset of triple negative. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

EnABLing Tumor Growth and Progression: Recent progress in unraveling the functions of ABL kinases in solid tumor cells. [2022]

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

The Emerging Role of ABL Kinases in Solid Tumors. [2022]

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

AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. [2023]