Antibody-Drug Conjugate for Advanced Cancer

Recruiting at 15 trial locations

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

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: MBrace Therapeutics

Must not be taking: Strong CYP3A

Disqualifiers: Neuropathy, CNS metastases, others

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

Compensation: Varies

Number of Visits: Unknown

130 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called MBRC-101, an antibody-drug conjugate, for individuals with advanced cancers unresponsive to standard treatments. The goal is to determine the optimal dose and evaluate the treatment's effectiveness and safety. Researchers will study various solid tumors, including specific lung and breast cancers. Individuals diagnosed with advanced cancer that does not respond to other treatments might be suitable candidates.

As a Phase 1 trial, participants will be among the first to receive this new treatment, aiding researchers in understanding its effects in people.

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.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

A previous study tested MBRC-101 on patients with advanced cancers unresponsive to standard treatments. The study aimed to determine the optimal dose patients could tolerate. Early findings examined how the body processed the drug and monitored for harmful side effects.

So far, MBRC-101 has shown promise in being well-tolerated, as patients did not experience serious or unexpected side effects at certain doses. Researchers continue to seek the best dose that balances effectiveness with minimal side effects. Information from these studies helps ensure that MBRC-101 can be a safe option for future treatments. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for advanced cancer, which often include chemotherapy and radiation, MBRC-101 is an antibody-drug conjugate that targets cancer cells more precisely. Researchers are excited because MBRC-101 combines a monoclonal antibody with a powerful anti-cancer drug, allowing it to directly deliver the drug to cancer cells while sparing healthy cells. This targeted approach not only has the potential to reduce side effects but also aims to improve treatment effectiveness by ensuring that more of the drug reaches the cancer cells. By offering a more precise attack on cancer cells, MBRC-101 could lead to better outcomes for patients with advanced cancer.

What evidence suggests that MBRC-101 might be an effective treatment for advanced cancer?

Research has shown that MBRC-101, which participants in this trial may receive, could be a promising treatment for advanced cancers. This treatment combines an antibody with a cancer-fighting drug. In early lab studies, MBRC-101 targeted a protein called EphA5, found in some cancer cells, and successfully delivered the drug directly into these cells. This targeted method showed potential in early tests to kill cancer cells while sparing healthy cells. Although more research with people is needed, these early results offer hope for those with advanced cancers that haven't responded to other treatments. ^{1 2 3 5 6}

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• MBRC-101

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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]

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 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 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]

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]

Citations

1. sciencedirect.com sciencedirect.com/science/article/pii/S155608642401311X

P2.10A.02 Phase 1/1b Trial of MBRC-101, An Anti-EphA5 ... This Phase 1/1b trial is evaluating MBRC-101, a novel ADC composed of an anti-EphA5 antibody and MMAE payload, in patients with NSCLC and other advanced ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06014658

Study Details | NCT06014658 | Safety, PK, and Preliminary ... This is a first-in-human (FIH), open label Phase 1/1b / Phase 2 study in patients with advanced metastatic solid tumors refractory to standard treatment.

3. aacrjournals.org aacrjournals.org/cancerres/article/84/9_Supplement/PO3-18-04/744991/Abstract-PO3-18-04-MBRC-101-a-novel-antibody-drug

Abstract PO3-18-04: MBRC-101: a novel antibody-drug ... We investigated the expression of EphA5 in breast cancer (BC) and assessed EphA5 as a potential cancer-specific target using a novel ADC designated MBRC-101.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12259246/

First-generation and preclinical evaluation of an EphA5 ... Here, we report the design and preclinical evaluation of MBRC-101, a first-in-class antibody-drug conjugate (ADC) targeting EphA5, a receptor ...

5. mbracetrx.com mbracetrx.com/clinical-program-mbrc-101/

Clinical Program MBRC-101 Pre-clinical data has shown the ability of EphA5 to bind antibody and to internalize the antibody with its conjugate drug into the cancer cell. Robust pre- ...

6. cancer.columbia.edu cancer.columbia.edu/cancer-types-care/clinical-trials/find-clinical-trial/multicenter-open-label-phase-1-1b-dose-finding-safety-and-pharmacokinetic-study-mbrc-101-anti-epha5-monomethyl-auristatin-e-mmae-antibody-drug-conjugate-advanced-refractory-solid-tumors

A MULTICENTER, OPEN-LABEL PHASE 1/1B DOSE ... The purpose of this research is to determine the dose and dosing regimens of an investigational drug, MBRC-101, that are well tolerated, as well as to evaluate ...