Antibody-Drug Conjugate for Advanced Cancer

Recruiting at 15 trial locations

Overseen By Kellogg Parsons, MD, M.H.S.

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: MBrace Therapeutics

Must not be taking: Strong CYP3A

Disqualifiers: Neuropathy, CNS metastases, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial is testing MBRC-101, a new drug, in patients with advanced cancers that haven't improved with other treatments. It aims to find the best dose and check its safety and effectiveness. The study will also observe how the drug behaves in the body and if it causes any immune reactions.

Will I have to stop taking my current medications?

The trial requires that any anticancer therapy must be stopped at least 14 days before the first dose of the study drug. If you are taking strong CYP3A inhibitors or inducers, these must also be stopped 14 days prior to the study. Other medications are not specifically mentioned, so it's best to discuss with the study team.

What data supports the effectiveness of the drug MBRC-101 for advanced cancer?

Research on similar drugs shows that monomethyl auristatin E (MMAE), when linked to antibodies, can effectively target and kill cancer cells. This approach has been successful in treating certain types of tumors by delivering the drug directly to cancer cells, minimizing damage to healthy cells. ^{1 2 3 4 5}

What safety data exists for the antibody-drug conjugate MBRC-101 (Anti-EphA5 MMAE)?

Research on similar antibody-drug conjugates using MMAE shows that they can have off-target toxicity, but new designs with non-cleavable linkers may improve safety by reducing this effect. A study on a related ADC showed improved safety with lower toxicity to normal tissues, suggesting potential for safer use in humans. ^{1 2 6 7 8}

What makes the drug MBRC-101 unique for treating advanced cancer?

MBRC-101 is unique because it targets the EphA5 receptor, which is highly expressed in some solid tumors, using an antibody-drug conjugate (ADC) that combines a specific antibody with a powerful cancer-killing agent, monomethyl auristatin E (MMAE). This approach allows for targeted delivery of the drug to cancer cells, potentially reducing damage to healthy cells compared to traditional chemotherapy. ^{1 2 3 5 8}

Eligibility Criteria

Adults with advanced solid tumors that no longer respond to standard treatments can join this trial. They must have a life expectancy of at least 3 months, be able to give informed consent, and agree to use effective contraception. Specific criteria apply for different phases and cohorts regarding tumor type and expression of a protein called EphA5.

Inclusion Criteria

For Phase 1b dose expansion: i. Cohort A: Histologic or cytologic diagnosis of NSLC (adenocarcinoma and SCC). ii. Cohort B: Histologic or cytologic diagnosis of TNBC or HR positive, HER2 negative breast cancer. iii. Cohort C: Histologic or cytologic diagnosis of solid tumors irrespective of histologic tissue type (i.e., tumor agnostic), excluding NSCLC and breast cancer. The Sponsor may add or remove specific tumor indications based on emerging, real-time study data.

Hematologic function, as follows (no red blood cell (RBC) or platelet transfusions are allowed within 14 days of the first dose of MBRC-101): Absolute neutrophil count (ANC) ≥ 1.0 × 109/L Platelet count ≥ 75 × 109/L Hemoglobin ≥ 9 g/dL Creatinine clearance of ≥ 30 mL/min by the Cockcroft-Gault equation or as measured by 24-hour urine collection. Total bilirubin ≤ 1.5 × upper limit normal (ULN). AST ≤ 3.0 × ULN. ALT ≤ 3.0 × ULN. International normalised ratio (INR) < 1.5 (or ≤ 3.0 if on therapeutic anticoagulation). Treatment with other agents for cancer, if received, must have been discontinued ≥ 2 weeks prior to first dose of study drug. Prior ADC therapy is allowed. Prior agents conjugated to MMAE are allowed for Phase 1 but not Phase 1b.

I am a male and agree to use two forms of birth control, including a barrier method, during and for 6 months after the study.

Exclusion Criteria

I do not have any eye conditions that could put me at risk during the study.

Use of any investigational drug within 14 days prior to the first dose of study drug.

A baseline QT interval as corrected by Fridericia's formula (QTcF) > 450 msec.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Dose Escalation

Identify potential optimal biologically relevant doses (OBRD) and the maximum tolerated dose (MTD) of MBRC-101

21 days

Regular visits for dose escalation monitoring

Phase 1b Expansion

Evaluate the safety and preliminary clinical activity of MBRC-101 at potential OBRDs

Up to 24 months

Regular visits for safety and efficacy evaluation

Phase 2

Evaluate anti-tumor activity and safety of the RP2D determined during Phase 1b

Up to 24 months

Regular visits for efficacy evaluation

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• MBRC-101 (Monoclonal Antibodies)

Trial Overview MBRC-101, an antibody-drug conjugate, is being tested in patients with refractory cancer. The study has two parts: Phase 1 determines the safest dose levels; Phase 1b assesses safety further and looks for signs of effectiveness. Participants' reactions to the drug are closely monitored over time.

Participant Groups

Group I: Phase 2 Experimental Treatment 1 Intervention

Group II: Phase 1b Expansion Experimental Treatment 1 Intervention

Group III: Phase 1 Dose Escalation Experimental Treatment 1 Intervention

Who Is Running the Clinical Trial?

MBrace Therapeutics

Lead Sponsor

Trials

1

Recruited

130+

Findings from Research

The phase 1 study of MEDI-547, an antibody drug conjugate targeting the EphA2 receptor in solid tumors, was halted due to significant treatment-related adverse events, including bleeding and liver disorders, indicating serious safety concerns.

Out of six patients treated, 83.3% experienced disease progression, and the study could not determine a maximum tolerated dose (MTD) due to the early termination, suggesting that MEDI-547 may not be a viable option for further clinical development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1, open-label study of MEDI-547 in patients with relapsed or refractory solid tumors. Annunziata, CM., Kohn, EC., LoRusso, P., et al.[2021]

The study found that antibody-drug conjugates (ADCs) with different drug loading ratios showed varying potency against CD30(+) malignant cells, with higher drug loading (E8) being more potent in vitro but not necessarily more effective in vivo compared to lower loading (E4).

Reducing the drug loading per antibody increased the therapeutic index, suggesting that ADC design should consider optimal drug loading to balance efficacy and safety, as E4 demonstrated comparable antitumor activity to E8 while requiring a lower dose and having a better safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of drug loading on the antitumor activity of a monoclonal antibody drug conjugate. Hamblett, KJ., Senter, PD., Chace, DF., et al.[2021]

The study developed new antibody-drug conjugates (ADCs) using auristatins, specifically focusing on monomethylauristatin F (MMAF), which showed improved potency through the use of innovative dipeptide linkers.

By modifying the C-terminal peptide sequence of the auristatins, researchers were able to create ADCs with significantly enhanced therapeutic indices, indicating a better balance between efficacy and safety in targeting tumor cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel peptide linkers for highly potent antibody-auristatin conjugate. Doronina, SO., Bovee, TD., Meyer, DW., et al.[2020]

The study demonstrated that the new antibody-drug conjugate (ADC) cAC10-L4-MMAF is highly potent against CD30 positive tumors, showing similar efficacy to the previously tested cAC10-L1-MMAF while being tolerated at doses over three times higher than the maximum tolerated dose (MTD) of the latter.

The research highlights the importance of linker design in ADCs, as modifications to the linker can significantly enhance the therapeutic index, improving both efficacy and safety profiles for treatments targeting difficult-to-access tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enhanced activity of monomethylauristatin F through monoclonal antibody delivery: effects of linker technology on efficacy and toxicity. Doronina, SO., Mendelsohn, BA., Bovee, TD., et al.[2020]

The study developed a novel antibody-drug conjugate, RC68-MC-VC-PAB-MMAE, which effectively targets and inhibits the growth of non-small cell lung cancer (NSCLC) cells expressing the epidermal growth factor receptor (EGFR), showing strong antitumor activity in vitro and in vivo without affecting the body weight of mice.

RC68-MC-VC-PAB-MMAE demonstrated a stronger antitumor effect compared to another conjugate, RC68-PY-VC-PAB-MMAE, and was more effective than the standard chemotherapy drug docetaxel, suggesting its potential as a promising treatment for EGFR-positive NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monomethyl auristatin E-conjugated anti-EGFR antibody inhibits the growth of human EGFR-positive non-small cell lung cancer. Li, Z., Wang, M., Yu, D., et al.[2020]

A physiologically based pharmacokinetic (PBPK) model was successfully developed to predict drug-drug interactions (DDIs) for monomethyl auristatin E (MMAE) released from valine-citrulline-MMAE antibody-drug conjugates (ADCs), using data from both in vitro and in vivo studies.

The model accurately simulated the pharmacokinetics of MMAE and predicted DDIs with other drugs, demonstrating its potential for assessing DDI risks in clinical development of MMAE-based therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Physiologically based pharmacokinetic modeling as a tool to predict drug interactions for antibody-drug conjugates. Chen, Y., Samineni, D., Mukadam, S., et al.[2021]

Monomethyl auristatin E (MMAE) linked to ionized L-Cysteine (Cys) shows high potency and can effectively enter tumor cells while minimizing off-target toxicity, making it a promising alternative for antibody-drug conjugates (ADCs).

The novel Cys-linker-MMAE ADC (mil40-15) demonstrated excellent plasma stability and maintained potent cytotoxicity with a maximum tolerated dose similar to that of naked antibodies, indicating improved safety and efficacy compared to traditional MMAE-based ADCs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antibody-Drug Conjugate Using Ionized Cys-Linker-MMAE as the Potent Payload Shows Optimal Therapeutic Safety. Wang, Y., Liu, L., Fan, S., et al.[2020]

The humanized Fab fragment ABC3315 significantly enhances the selectivity of monomethyl auristatin E (MMAE) by increasing its IC50 against human cancer cell lines by over 500-fold, reducing off-target toxicity without affecting the efficacy of MMAE antibody-drug conjugates (ADCs).

Coadministration of ABC3315 with MMAE ADCs resulted in improved safety profiles, as it prevented significant drops in white and red blood cell counts and reduced body weight loss in treated mice, indicating a better therapeutic window for cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Payload-Binding Fab Fragments Increase the Therapeutic Index of MMAE Antibody-Drug Conjugates. Bordeau, BM., Nguyen, TD., Polli, JR., et al.[2023]

References

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

Phase 1, open-label study of MEDI-547 in patients with relapsed or refractory solid tumors. [2021]

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

Effects of drug loading on the antitumor activity of a monoclonal antibody drug conjugate. [2021]

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

Novel peptide linkers for highly potent antibody-auristatin conjugate. [2020]

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

Enhanced activity of monomethylauristatin F through monoclonal antibody delivery: effects of linker technology on efficacy and toxicity. [2020]

5. Germany pubmed.ncbi.nlm.nih.gov

Monomethyl auristatin E-conjugated anti-EGFR antibody inhibits the growth of human EGFR-positive non-small cell lung cancer. [2020]

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

Physiologically based pharmacokinetic modeling as a tool to predict drug interactions for antibody-drug conjugates. [2021]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Antibody-Drug Conjugate Using Ionized Cys-Linker-MMAE as the Potent Payload Shows Optimal Therapeutic Safety. [2020]

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

Payload-Binding Fab Fragments Increase the Therapeutic Index of MMAE Antibody-Drug Conjugates. [2023]