XMT-1660 for Breast Cancer
Recruiting in Palo Alto (17 mi)
+20 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Mersana Therapeutics
Must not be taking: Auristatin ADCs
Disqualifiers: Untreated CNS metastases, Cirrhosis, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This trial tests a new drug called XMT-1660 to see if it is safe and what side effects it might have. It focuses on patients whose cancer has come back, spread locally, or spread throughout the body. The study will first find a safe dose and then check if this dose helps treat solid tumors.
Will I have to stop taking my current medications?
The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that you should not have had major surgery or certain cancer treatments recently, so it's best to discuss your specific medications with the trial team.
What data supports the effectiveness of the drug XMT-1660 for breast cancer?
Research shows that XMT-1660, a drug designed to target a protein called B7-H4, has been effective in causing complete tumor regressions in breast cancer models. It works by delivering a powerful cancer-killing agent directly to the cancer cells, and its effectiveness is linked to the presence of B7-H4 in the tumors.
12345What safety data exists for XMT-1660 in humans?
XMT-1660, a B7-H4-targeted antibody-drug conjugate, has entered clinical development in a phase I study to assess its safety in humans. Preclinical studies showed it caused complete tumor regressions in models of breast cancer, and its safety profile is being evaluated in ongoing trials.
12678What makes the drug XMT-1660 unique for treating breast cancer?
XMT-1660 is unique because it is an antibody-drug conjugate (ADC) that specifically targets the B7-H4 protein, which is overexpressed in certain breast cancers. This allows for targeted delivery of the drug to cancer cells, potentially leading to better outcomes and fewer side effects compared to non-targeted therapies.
12679Eligibility Criteria
This trial is for adults with certain advanced solid tumors like ovarian, breast, endometrial, fallopian tube, or peritoneal cancer. They should be in good physical condition (ECOG 0-1), have at least one measurable tumor lesion and agree to a biopsy if safe. Not eligible if they've had another cancer treatment within 2 years (except some skin cancers or localized treatments), severe diseases that could affect the study's process, major surgery or anticancer therapy too close to the start of this study, untreated brain metastases, or prior specific ADC treatments.Inclusion Criteria
I have had a brain MRI recently or will have one due to my triple-negative breast cancer or symptoms/history of brain metastases.
My cancer has returned or spread and didn't respond to treatment or I couldn't tolerate the treatment.
I am fully active or restricted in physically strenuous activity but can do light work.
+2 more
Exclusion Criteria
I have a serious heart condition.
I have a history of serious liver conditions.
I do not have any severe illnesses that could worsen my condition or affect the study.
+5 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Dose Escalation
Determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of XMT-1660
17 months
Dose Expansion
Use the dose found in the Dose Escalation phase to assess the safety and efficacy of XMT-1660 in treating solid tumor cancers
3 years
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The clinical trial is testing XMT-1660's effectiveness on participants with various types of solid tumors. The main focus is to see how well it works against these cancers and what effects it has on patients' bodies.
1Treatment groups
Experimental Treatment
Group I: XMT-1660Experimental Treatment1 Intervention
Single arm XMT-1660 alone (monotherapy)
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Summit Cancer CentersSpokane, WA
Avera Cancer InstituteSioux Falls, SD
ICHAN School of Medicine at Mount SinaiNew York, NY
MD AndersonHouston, TX
More Trial Locations
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Who Is Running the Clinical Trial?
Mersana TherapeuticsLead Sponsor
References
Discovery and Preclinical Characterization of XMT-1660, an Optimized B7-H4-Targeted Antibody-Drug Conjugate for the Treatment of Cancer. [2023]Antibody-drug conjugates (ADC) achieve targeted drug delivery to a tumor and have demonstrated clinical success in many tumor types. The activity and safety profile of an ADC depends on its construction: antibody, payload, linker, and conjugation method, as well as the number of payload drugs per antibody [drug-to-antibody ratio (DAR)]. To allow for ADC optimization for a given target antigen, we developed Dolasynthen (DS), a novel ADC platform based on the payload auristatin hydroxypropylamide, that enables precise DAR-ranging and site-specific conjugation. We used the new platform to optimize an ADC that targets B7-H4 (VTCN1), an immune-suppressive protein that is overexpressed in breast, ovarian, and endometrial cancers. XMT-1660 is a site-specific DS DAR 6 ADC that induced complete tumor regressions in xenograft models of breast and ovarian cancer as well as in a syngeneic breast cancer model that is refractory to PD-1 immune checkpoint inhibition. In a panel of 28 breast cancer PDXs, XMT-1660 demonstrated activity that correlated with B7-H4 expression. XMT-1660 has recently entered clinical development in a phase I study (NCT05377996) in patients with cancer.
An anti-B7-H4 antibody-drug conjugate for the treatment of breast cancer. [2022]B7-H4 has been implicated in cancers of the female reproductive system and investigated for its possible use as a biomarker for cancer, but there are no preclinical studies to demonstrate that B7-H4 is a molecular target for therapeutic intervention of cancer. We provide evidence that the prevalence and expression levels of B7-H4 are high in different subtypes of breast cancer and that only a few normal tissues express B7-H4 on the cell membrane. These profiles of low normal expression and upregulation in cancer provide an opportunity for the use of antibody-drug conjugates (ADCs), cytotoxic drugs chemically linked to antibodies, for the treatment of B7-H4 positive cancers. We have developed an ADC specific to B7-H4 that uses a linker drug consisting of a potent antimitotic, monomethyl auristatin E (MMAE), linked to engineered cysteines (THIOMAB) via a protease labile linker. We will refer to ADCs that use the THIOMAB format as TDCs to help distinguish the format from standard MC-vc-MMAE ADCs that are conjugated to the interchain disulfide bonds. Anti-B7-H4 (h1D11)-MC-vc-PAB-MMAE (h1D11 TDC) produced durable tumor regression in cell line and patient-derived xenograft models of triple-negative breast cancer. It also binds rat B7-H4 with similar affinity to human and allowed us to test for target dependent toxicity in rats. We found that our anti-B7-H4 TDC has toxicity findings similar to untargeted TDC. Our results validate B7-H4 as an ADC target for breast cancer and support the possible use of this TDC in the treatment of B7-H4(+) breast cancer.
Clinical Development of New Antibody-Drug Conjugates in Breast Cancer: To Infinity and Beyond. [2022]Metastatic breast cancer remains an incurable disease, and new therapies are needed. One major limitation of chemotherapy is the toxicity associated with higher dose exposure. Antibody-drug conjugates (ADCs) are a complex and evolving class of agents specifically designed with the objective of delivering antineoplastic medicines in the most precise and selectively targeted way. ADCs are composed of four key components: (1) the target antigen, (2) an antibody construct, (3) a payload (most commonly a cytotoxic agent), and (4) a linker moiety that couples the payload and the antibody. In this review, we discuss the clinical development of ADCs for the treatment of breast cancer, focusing on two recently FDA-approved agents, trastuzumab deruxtecan and sacituzumab govitecan, and discuss the ongoing efforts exploring new agents. Finally, we summarize the current portfolio of clinical trials that could change the algorithm of treatment for early and advanced breast cancer.
Managing adverse events of sacituzumab govitecan. [2023]The development of antibody-drug conjugates (ADCs) have revolutionized treatment for breast cancer. Sacituzumab govitecan (SG), a Trop2-targeted ADC, has demonstrated remarkable efficacy in triple-negative breast cancer (TNBC) and hormone receptor-positive metastatic breast cancer.
Antibody-Drug Conjugates in HR+ Breast Cancer: Where Are We Now and Where Are We Heading? [2023]Hormone receptor-positive (HR+) breast cancer (BC) accounts for about 60-70% of all diagnosed BCs, and endocrine therapy has long been the hallmark of systemic treatment for this tumor subtype. However, the therapeutic paradigm of luminal BC has been overcome due to recent evidence of antibody-drug conjugate (ADC) activity (such as trastuzumab deruxtecan and sacituzumab govitecan) in pretreated metastatic HR+ BC patients. Therefore, nowadays, the identification of patients who can benefit more from this approach represents a new challenge, as does the management of new toxicities and the integration of these drugs into the therapeutic algorithm of HR+ metastatic BC patients.
A phase I dose escalation study with anti-CD44v6 bivatuzumab mertansine in patients with incurable squamous cell carcinoma of the head and neck or esophagus. [2022]To assess safety, pharmacokinetics, maximum tolerated dose, and preliminary efficacy of bivatuzumab mertansine. Bivatuzumab is a humanized monoclonal antibody directed against CD44v6, which previously seemed to be safe in phase I radioimmunotherapy trials, whereas the conjugated mertansine is a potent maytansine derivative.
Trastuzumab Deruxtecan Data Impresses at ESMO. [2022]The DESTINY-Breast03 study, a randomized, phase III trial pitting the antibody-drug conjugates trastuzumab emtansine and trastuzumab deruxtecan against each other in HER2+ metastatic breast cancer, found remarkable improvements in efficacy and safety for the latter, newer therapy.
Cantuzumab mertansine, a maytansinoid immunoconjugate directed to the CanAg antigen: a phase I, pharmacokinetic, and biologic correlative study. [2016]To determine the maximum tolerated dose and pharmacokinetics of cantuzumab mertansine, an immunoconjugate of the potent maytansine derivative (DM1) and the humanized monoclonal antibody (huC242) directed to CanAg, intravenously (i.v.) once every 3 weeks and to seek evidence of antitumor activity.
A Biparatopic Antibody-Drug Conjugate to Treat MET-Expressing Cancers, Including Those that Are Unresponsive to MET Pathway Blockade. [2023]Lung cancers harboring mesenchymal-to-epithelial transition factor (MET) genetic alterations, such as exon 14 skipping mutations or high-level gene amplification, respond well to MET-selective tyrosine kinase inhibitors (TKI). However, these agents benefit a relatively small group of patients (4%-5% of lung cancers), and acquired resistance limits response durability. An antibody-drug conjugate (ADC) targeting MET might enable effective treatment of MET-overexpressing tumors (approximately 25% of lung cancers) that do not respond to MET targeted therapies. Using a protease-cleavable linker, we conjugated a biparatopic METxMET antibody to a maytansinoid payload to generate a MET ADC (METxMET-M114). METxMET-M114 promotes substantial and durable tumor regression in xenografts with moderate to high MET expression, including models that exhibit innate or acquired resistance to MET blockers. Positron emission tomography (PET) studies show that tumor uptake of radiolabeled METxMET antibody correlates with MET expression levels and METxMET-M114 efficacy. In a cynomolgus monkey toxicology study, METxMET-M114 was well tolerated at a dose that provides circulating drug concentrations that are sufficient for maximal antitumor activity in mouse models. Our findings suggest that METxMET-M114, which takes advantage of the unique trafficking properties of our METxMET antibody, is a promising candidate for the treatment of MET-overexpressing tumors, with the potential to address some of the limitations faced by the MET function blockers currently in clinical use.