GEN1042 for Advanced Cancers
Recruiting in Palo Alto (17 mi)
+78 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Waitlist Available
Sponsor: Genmab
No Placebo Group
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?This trial is testing a new drug called GEN1042 to see if it can help treat advanced cancer. It focuses on patients whose cancer has spread or is hard to treat. The goal is to find out if GEN1042 can safely reduce or stop tumor growth.
Do I have to stop taking my current medications for the trial?
The trial requires stopping anti-cancer agents at least 21 days or 5 half-lives before starting GEN1042. Other medications, like corticosteroids or immunosuppressive drugs, must be stopped 14 days before treatment. The protocol does not specify other medications, so consult your doctor.
What data supports the idea that GEN1042 for Advanced Cancers is an effective treatment?
The available research shows that GEN1042, a drug targeting CD40 and 4-1BB on immune cells, is well tolerated and active in patients with advanced solid tumors. This suggests it could be an effective treatment for these cancers. While other treatments like MEDI5752 also show promise, GEN1042 specifically enhances the body's immune response against tumors, which is a key factor in its effectiveness.
12345What safety data is available for GEN1042 in treating advanced cancers?
Preliminary findings from a first-in-human phase I/II trial of GEN1042 suggest that the drug is well tolerated in patients with advanced solid tumors. Additionally, bispecific antibodies like GEN1042 have been designed to target CD40 activation preferentially to dendritic cells, which may offer a superior safety profile compared to traditional CD40 agonists, reducing dose-limiting toxicities.
12678Is the drug GEN1042 a promising treatment for advanced cancers?
Yes, GEN1042 is a promising drug for advanced cancers. It is a special type of antibody that targets two important proteins on immune cells, CD40 and 4-1BB, which helps the immune system fight cancer. Early studies show that it is well tolerated by patients and can activate the immune system to attack tumors effectively.
12369Eligibility Criteria
Adults with certain advanced cancers (melanoma, NSCLC, CRC, HNSCC, PDAC) that have relapsed or are untreatable with no standard therapy available. Participants must be in good physical condition and have not had recent cancer treatments or surgeries. Those with autoimmune diseases, severe allergies to monoclonal antibodies, ongoing pneumonitis, or requiring high-dose steroids are excluded.Inclusion Criteria
Measurable disease according to RECIST 1.1
I am 18 years old or older.
My lung cancer is advanced, and I haven't had any cancer treatments yet.
+10 more
Exclusion Criteria
I still have side effects from past cancer treatments.
I haven't taken cancer drugs within the last 21 days or 5 half-lives before starting GEN1042.
I haven't had chemotherapy, biological therapy, or major surgery within the last 3 weeks or 5 half-lives of the drug before starting the trial.
+6 more
Participant Groups
The trial is testing GEN1042's safety and effectiveness against tumors when used alone or combined with other cancer drugs like Paclitaxel and Pembrolizumab. It targets patients who've exhausted standard treatments for their metastatic solid tumors.
2Treatment groups
Experimental Treatment
Group I: Monotherapy - Dose Escalation and Dose Expansion PartsExperimental Treatment1 Intervention
Group II: Combination Therapy - Safety Run-in and Expansion PartsExperimental Treatment9 Interventions
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
City of HopeDuarte, CA
Hope and Healing Cancer ServicesHinsdale, IL
Washington University School of MedicineSaint Louis, MO
ChristianaCareNewark, DE
More Trial Locations
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Who Is Running the Clinical Trial?
GenmabLead Sponsor
BioNTech SEIndustry Sponsor
References
Dual-Targeting Approach for CD40 and 4-1BB. [2022]Preliminary findings from a first-in-human phase I/II trial of GEN1042, a bispecific antibody that simultaneously targets CD40 and 4-1BB on immune cells, suggest that this drug is well tolerated and active in patients with advanced solid tumors.
DuoBody-CD40x4-1BB induces dendritic-cell maturation and enhances T-cell activation through conditional CD40 and 4-1BB agonist activity. [2022]Despite the preclinical promise of CD40 and 4-1BB as immuno-oncology targets, clinical efforts evaluating CD40 and 4-1BB agonists as monotherapy have found limited success. DuoBody-CD40×4-1BB (GEN1042/BNT312) is a novel investigational Fc-inert bispecific antibody for dual targeting and conditional stimulation of CD40 and 4-1BB to enhance priming and reactivation of tumor-specific immunity in patients with cancer.
Preclinical studies combining bispecific antibodies with cytokine-stimulated effector cells for immunotherapy of renal cell carcinoma. [2018]Bispecific antibodies--consisting of a F(ab')-fragment derived from a monoclonal antibody against a tumor epitope as well as of another antibody against a cytotoxic trigger molecule on immune effector cells--can improve the effectiveness of antibody-based tumor therapy.
MEDI5752 Suppresses Two Immune Checkpoints. [2022]Preliminary data from a phase I trial of MEDI5752, a bispecific antibody targeting both PD-1 and CTLA4, indicate the drug is well tolerated and active, with durable responses seen across diverse tumor types.
XFab-α4-1BB/CD40L fusion protein activates dendritic cells, improves expansion of antigen-specific T cells, and exhibits antitumour efficacy in multiple solid tumour models. [2023]Additional immunotherapies are still warranted for non-responders to checkpoint inhibitors with refractory or relapsing cancers, especially for patients with "cold" tumours lacking significant immune infiltration at treatment onset. We developed XFab-α4-1BB/CD40L, a bispecific antibody targeting 4-1BB and CD40 for dendritic cell activation and priming of tumour-reactive T cells to inhibit tumours.
Bispecific antibodies increase the therapeutic window of CD40 agonists through selective dendritic cell targeting. [2022]Therapeutic use of agonistic anti-CD40 antibodies is a potentially powerful approach for activation of the immune response to eradicate tumors. However, the translation of this approach to clinical practice has been substantially restricted due to the severe dose-limiting toxicities observed in multiple clinical trials. Here, we demonstrate that conventional type 1 dendritic cells are essential for triggering antitumor immunity but not the toxicity of CD40 agonists, while macrophages, platelets and monocytes lead to toxic events. Therefore, we designed bispecific antibodies that target CD40 activation preferentially to dendritic cells, by coupling the CD40 agonist arm with CD11c-, DEC-205- or CLEC9A-targeting arms. These bispecific reagents demonstrate a superior safety profile compared to their parental CD40 monospecific antibody while triggering potent antitumor activity. We suggest such cell-selective bispecific agonistic antibodies as a drug platform to bypass the dose-limiting toxicities of anti-CD40, and of additional types of agonistic antibodies used for cancer immunotherapy.
Fc Engineering for Developing Therapeutic Bispecific Antibodies and Novel Scaffolds. [2019]Therapeutic monoclonal antibodies have become molecules of choice to treat autoimmune disorders, inflammatory diseases, and cancer. Moreover, bispecific/multispecific antibodies that target more than one antigen or epitope on a target cell or recruit effector cells (T cell, natural killer cell, or macrophage cell) toward target cells have shown great potential to maximize the benefits of antibody therapy. In the past decade, many novel concepts to generate bispecific and multispecific antibodies have evolved successfully into a range of formats from full bispecific immunoglobulin gammas to antibody fragments. Impressively, antibody fragments such as bispecific T-cell engager, bispecific killer cell engager, trispecific killer cell engager, tandem diabody, and dual-affinity-retargeting are showing exciting results in terms of recruiting and activating self-immune effector cells to target and lyse tumor cells. Promisingly, crystallizable fragment (Fc) antigen-binding fragment and monomeric antibody or half antibody may be particularly advantageous to target solid tumors owing to their small size and thus good tissue penetration potential while, on the other hand, keeping Fc-related effector functions such as antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, antibody-dependent cell-mediated phagocytosis, and extended serum half-life via interaction with neonatal Fc receptor. This review, therefore, focuses on the progress of Fc engineering in generating bispecific molecules and on the use of small antibody fragment as scaffolds for therapeutic development.
Multiformat T-cell-engaging bispecific antibodies targeting human breast cancers. [2018]Four different formats of bispecific antibodies (bsAbs) were generated that consist of anti-Her2 IgG or Fab site-specifically conjugated to anti-CD3 Fab using the genetically encoded noncanonical amino acid. These bsAbs varied in valency or in the presence or absence of an Fc domain. Different valencies did not significantly affect antitumor efficacy, whereas the presence of an Fc domain enhanced cytotoxic activity, but triggered antigen-independent T-cell activation. We show that the bsAbs can efficiently redirect T cells to kill all Her2 expressing cancer cells, including Her2 1+ cancers, both in vitro and in rodent xenograft models. This work increases our understanding of the structural features that affect bsAb activity, and underscores the potential of bsAbs as a promising therapeutic option for breast cancer patients with low or heterogeneous Her2 expression.
Binding characteristics and antitumor properties of 1A10 bispecific antibody recognizing gp40 and human transferrin receptor. [2007]The bispecific murine monoclonal antibody (MAb) 1A10 has specificity for the human transferrin receptor (TfR) and the human tumor-associated antigen gp40. This antibody, therefore, functions as an "antigen fork" by binding to two distinct antigens on the same malignant cell. Highly purified 1A10 inhibits the growth of cells coexpressing high levels of human TfR and the tumor-associated antigen gp40 by binding to both target antigens. In SW948 cells, the majority of 1A10 binding is via its gp40 specificity, and half-maximal inhibition of cell growth by 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay requires 20-30-micrograms/ml concentrations of 1A10. The binding of 1A10 correlates with growth inhibition in the cell lines HT-29, SK-OV-3, OVCAR-2, and OVCAR-3. The growth of OVCAR-10 cells, which express little gp40 and TfR, is not inhibited by 1A10. However, SK-BR-3 cells, which express abundant gp40 and extremely high levels of TfR, are insensitive to the effects of 1A10. In some cell lines, combined exposure to 1A10 and the iron chelator deferoxamine mesylate has synergistic antiproliferative effects. A single i.p. dose of 600 micrograms 1A10 is sufficient to achieve an estimated tumor concentration of at least 30 micrograms/ml for 7 days in C.B17/Icr-scid mice bearing SW948 human tumor xenografts. Treatment of scid mice bearing day 2 or day 4 SW948 xenografts with single or multiple 1A10 doses inhibits tumor growth in a dose-related fashion. Antitumor effects are not seen with therapy using either parental antibody of 1A10. The antiproliferative properties of 1A10 in tumor cells overexpressing gp40 and TfR suggest avenues for the development of new bispecific antibody-promoted treatment strategies.