ST-067-001 for Solid Tumors
Recruiting in Palo Alto (17 mi)
+6 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Simcha IL-18, Inc.
Must not be taking: Immunosuppressants, Corticosteroids
Disqualifiers: Autoimmune disorders, Brain metastases, Cardiovascular disease, others
No Placebo Group
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?This trial is testing a new drug called ST-067 on patients with certain types of cancer that have not responded to previous treatments. The goal is to find the safest and most effective dose and to see how well it works against these cancers.
Do I need to stop my current medications to join the trial?
The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you are on ongoing immunosuppressive therapy or have received systemic anticancer therapy within 4 weeks of starting the trial.
What data supports the effectiveness of the treatment ST-067, Decoy-Resistant IL-18, when used with immunotherapy for advanced cancers?
Research shows that a similar treatment using a combination of IL-12 and Decoy-Resistant IL-18 can enhance the body's immune response against tumors, especially when injected directly into the tumor. This combination helps activate specific immune cells that attack cancer cells, suggesting potential effectiveness for ST-067 in advanced cancers.
12345Is the combination of ST-067 (Decoy-Resistant IL-18) and immunotherapy safe for humans?
Research shows that when Decoy-Resistant IL-18 is used with IL-12 in mice, it can cause serious toxicity if given systemically, but is safer when injected directly into tumors. This suggests potential safety concerns if not administered carefully.
15678What makes the drug ST-067 unique for treating advanced cancers?
ST-067, also known as Decoy-Resistant IL-18, is unique because it is engineered to resist inhibition by IL-18BP, a decoy receptor that limits the effectiveness of traditional IL-18 therapies. This allows ST-067 to enhance the immune system's ability to fight tumors by promoting the activity of specific immune cells, such as CD8+ T cells and natural killer cells, which are crucial for attacking cancer cells.
356910Eligibility Criteria
Adults (≥18 years) with advanced or metastatic cancer, including melanoma and lung cancer, who've progressed after standard therapy or for whom no survival-prolonging standard care is available. Participants must be able to perform light work (ECOG status of 0 or 1), have at least one measurable lesion not previously treated by biopsy or radiation, and an accessible tumor for required biopsies.Inclusion Criteria
My cancer is one of the following types: melanoma, kidney, triple-negative breast, non-small cell lung, head and neck, or has high microsatellite instability.
My condition worsened despite standard treatments.
My tumor has not been biopsied or treated with radiation.
+10 more
Exclusion Criteria
I do not have serious heart, breathing, adrenal gland, or autoimmune conditions.
I have not had radiation therapy in the past two weeks.
I do not have serious heart, lung, immune system, or adrenal gland problems.
+4 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Phase 1a Dose Escalation
Determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of ST-067, administered by subcutaneous (SC) or intravenous (IV) dosing, with or without obinutuzumab pre-treatment.
28 days per cohort
Weekly visits for dosing
Phase 1 Combination Therapy
Dose escalation in combination with pembrolizumab to determine MTD using mTPI design.
28 days per cohort
Weekly visits for ST-067, every 3 weeks for pembrolizumab
Phase 2 Expansion
Evaluate the preliminary efficacy of ST-067 administered at the RP2D in various solid tumors using a Simon 2 stage design.
8-12 weeks per assessment
Tumor response assessment every 8-12 weeks
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The trial tests ST-067 as a subcutaneous injection alone and in combination with IV infusion obinutuzumab (Gazyva®) plus pembrolizumab (Keytruda). It's a multi-phase study starting with dose escalation to assess safety and preliminary effectiveness before moving on to Phase 2.
4Treatment groups
Experimental Treatment
Group I: Phase 2, ExpansionExperimental Treatment1 Intervention
Phase 2 will enroll patients aged 18 years or older diagnosed with the following solid tumors: melanoma, renal cell carcinoma (RCC), triple negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), and microsatellite instability-high (MSI-Hi) tumors at the RP2D.
Group II: Phase 1a, Dose Escalation, ST-067 SC + Obinutuzumab Pre-treatmentExperimental Treatment2 Interventions
Patients will be treated every week with ST-067 in all cohorts. The DLT period is 28 days after the initial dose of ST-067. According to the mTPI schema initially there will be 3 patients per cohort until the first DLT is observed at which point cohorts will be expanded according to the predetermined mTPI design.
The starting dose for ST-067 with obinutuzumab pre-treatment will be 120µg/kg. Obinutuzumab will be administered at 1000 mg daily via IV infusion on 2 consecutive days, with the first dose given at least 7 days prior to first dose of SC ST-067.
Group III: Phase 1a, Dose EscalationExperimental Treatment1 Intervention
In the Phase 1a monotherapy study, the starting dose of ST-067 will be 30 μg/kg, with a total of 7 dose level cohorts planned.
The starting dose for the IV infusion monotherapy dosing will be 60 µg/kg.
Patients will be treated every week with ST-067 in all cohorts. The DLT period is 28 days after the initial dose of ST-067. According to the mTPI schema initially there will be 3 patients per cohort until the first DLT is observed at which point cohorts will be expanded according to the predetermined mTPI design. Up to 12 patients will be treated at the RP2D.
Group IV: Phase 1 combination therapyExperimental Treatment2 Interventions
Phase 1 dose escalation in combination with pembrolizumab will start at a dose of 30 µg/kg of ST-067 and 200 mg every 3 weeks of pembrolizumab. Patients will be treated every week with ST-067 and every three weeks with pembrolizumab. The MTD will be determined based on the mTPI design.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Providence Cancer Institute Franz ClinicPortland, OR
Roswell Park Cancer InstituteBuffalo, NY
HonorHealth Research InstituteScottsdale, AZ
Yale Cancer CenterNew Haven, CT
More Trial Locations
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Who Is Running the Clinical Trial?
Simcha IL-18, Inc.Lead Sponsor
Merck Sharp & Dohme LLCIndustry Sponsor
References
Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning. [2021]Adoptive cell therapy with tumor-targeted T cells is a promising approach to cancer therapy. Enhanced clinical outcome using this approach requires conditioning regimens with total body irradiation, lymphodepleting chemotherapy, and/or additional cytokine support. However, the need for prior conditioning precludes optimal application of this approach to a significant number of cancer patients intolerant to these regimens. Herein, we present preclinical studies demonstrating that treatment with CD19-specific, chimeric antigen receptor (CAR)-modified T cells that are further modified to constitutively secrete IL-12 are able to safely eradicate established disease in the absence of prior conditioning. We demonstrate in a novel syngeneic tumor model that tumor elimination requires both CD4(+) and CD8(+) T-cell subsets, autocrine IL-12 stimulation, and subsequent IFNγ secretion by the CAR(+) T cells. Importantly, IL-12-secreting, tumor-targeted T cells acquire intrinsic resistance to T regulatory cell-mediated inhibition. Based on these preclinical data, we anticipate that adoptive therapy using CAR-targeted T cells modified to secrete IL-12 will obviate or reduce the need for potentially hazardous conditioning regimens to achieve optimal antitumor responses in cancer patients.
Vaccination with IL-18 gene-modified, superantigen-coated tumor cells elicits potent antitumor immune response. [2019]To investigate the induction of antitumor immune response by vaccination with interleukin-18 (IL-18) gene-modified, C215Fab-SEA-coated tumor cells.
[Treatment of spontaneous metastatic lung cancer with tumor antigen-pulsed, interleukin-18 gene-modified dendritic cells]. [2012]To investigate the effect of tumor antigen-pulsed, interleukin-18 (IL-18) gene-modified dendritic cells in treatment of spontaneous metastatic lung cancer.
Human dendritic cells engineered to secrete interleukin-18 activate MAGE-A3-specific cytotoxic T lymphocytes in vitro. [2012]Adoptive cell transfer (ACT) involves the administration of tumor specific cytotoxic T lymphocytes (CTLs) into a patient to kill cancer cells. Although a promising cancer therapy, limitations on the generation of activated CTLs have restricted ATC's clinical application. Interleukin-18 (IL-18) is an interferon-γ (IFN-γ) inducing factor that plays an important functional role in regulating CTLs. Here, we attempt to use dendritic cells (DCs) modified with a recombinant adenovirus encoding IL-18 (rAd/IL-18) to improve the generation of activated tumor-specific CTLs. These engineered DCs secrete IL-18, increase the expression of co-stimulatory molecules, and enhance the cytotoxic efficacy of melanoma antigen 3 (MAGE-A3)-specific CTLs in vitro. We show that stimulation of CTLs with rAd/IL-18-loaded DCs increases the specific lysis of MAGE-A3-expressing human breast cancer MCF-7 cells, and at the same time increases the production of activated MAGE-A3-specific CTLs. Our results indicate that transducing DCs with rAd/IL-18 increases both the maturation of DCs and the activation level of MAGE-A3-specific CTLs, greatly enhancing the cytotoxic efficacy of CTLs towards tumor cells.
Intratumoral Gene Transfer of mRNAs Encoding IL12 in Combination with Decoy-Resistant IL18 Improves Local and Systemic Antitumor Immunity. [2023]IL12-based local gene therapy of cancer constitutes an active area of clinical research using plasmids, mRNAs, and viral vectors. To improve antitumor effects, we have experimentally tested the combination of mRNA constructs encoding IL12 and IL18. Moreover, we have used a form of IL18 [decoy-resistant IL18 (DR-18)] which has preserved bioactivity but does not bind to the IL18 binding protein decoy receptor. Both cytokines dramatically synergize to induce IFNγ release from mouse splenocytes, and, if systemically cotransferred to the liver, they mediate lethal toxicity. However, if given intratumorally to B16OVA tumor-bearing mice, the combination attains efficacy against the directly treated tumor and moderate tumor-delaying activity on distant noninjected lesions. Cotreatment was conducive to the presence of more activated CD8+ T cells in the treated and noninjected tumors. In keeping with these findings, the efficacy of treatment was contingent on the integrity of CD8+ T cells and cDC1 dendritic cells in the treated mice. Furthermore, efficacy of IL12 plus DR-18 local mRNA coinjection against distant concomitant tumors could be enhanced upon combination with anti-PD-1 mAb systemic treatment, thus defining a feasible synergistic immunotherapy strategy.
IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy. [2022]Cytokines were the first modern immunotherapies to produce durable responses in patients with advanced cancer, but they have only modest efficacy and limited tolerability1,2. In an effort to identify alternative cytokine pathways for immunotherapy, we found that components of the interleukin-18 (IL-18) pathway are upregulated on tumour-infiltrating lymphocytes, suggesting that IL-18 therapy could enhance anti-tumour immunity. However, recombinant IL-18 previously did not demonstrate efficacy in clinical trials3. Here we show that IL-18BP, a high-affinity IL-18 decoy receptor, is frequently upregulated in diverse human and mouse tumours and limits the anti-tumour activity of IL-18 in mice. Using directed evolution, we engineered a 'decoy-resistant' IL-18 (DR-18) that maintains signalling potential but is impervious to inhibition by IL-18BP. Unlike wild-type IL-18, DR-18 exerted potent anti-tumour effects in mouse tumour models by promoting the development of poly-functional effector CD8+ T cells, decreasing the prevalence of exhausted CD8+ T cells that express the transcriptional regulator of exhaustion TOX, and expanding the pool of stem-like TCF1+ precursor CD8+ T cells. DR-18 also enhanced the activity and maturation of natural killer cells to effectively treat anti-PD-1 resistant tumours that have lost surface expression of major histocompatibility complex class I molecules. These results highlight the potential of the IL-18 pathway for immunotherapeutic intervention and implicate IL-18BP as a major therapeutic barrier.
A newly discovered PD-L1 B-cell epitope peptide vaccine (PDL1-Vaxx) exhibits potent immune responses and effective anti-tumor immunity in multiple syngeneic mice models and (synergizes) in combination with a dual HER-2 B-cell vaccine (B-Vaxx). [2022]Blockade of checkpoint receptors with monoclonal antibodies against CTLA-4, PD-1 and PD-L1 has shown great clinical success in several cancer subtypes, yielding unprecedented responses albeit a significant number of patients develop resistance and remain refractory. Both PD-1/PD-L1 and HER-2 signaling pathway inhibitors have limited efficacy and exhibits significant toxicities that limit their use. Ongoing clinical studies support the need for rationale combination of immuno-oncology agents to make a significant impact in the lives of cancer patients. We introduce the development of a novel chimeric PD-L1 B-cell peptide epitope vaccine (amino acid 130-147) linked to a "promiscuous" T cell measles virus fusion (MVF) peptide (MVF-PD-L1(130); PDL1-Vaxx) or linked to tetanus toxoid (TT3) TT3-PD-L1 (130) via a linker (GPSL). These vaccine constructs are highly immunogenic and antigenic in several syngeneic animal models. The PD-L1 vaccines elicited high titers of polyclonal antibodies that inhibit tumor growth in multiple syngeneic cancer models, eliciting antibodies of different subtypes IgG1, IgG2a, IgG2b and IgG3, induced PD-1/PD-L1 blockade, decreased proliferation, induced apoptosis and caused ADCC of tumor cells. The PDL1-Vaxx induces similar inhibition of tumor growth versus the standard anti-mouse PD-L1 antibody in both syngeneic BALB/c and C57BL/6J mouse models. The combination of PDL1-Vaxx with HER-2 vaccine B-Vaxx demonstrated synergistic tumor inhibition in D2F2/E2 carcinoma cell line. The anti-PDL1-Vaxx block PD-1/PD-L1 interaction and significantly prolonged anti-tumor responses in multiple syngeneic tumor models. The combination of HER-2 vaccine (B-Vaxx) with either PDL1-Vaxx or PD1-Vaxx demonstrated synergistic tumor inhibition. PDL1-Vaxx is a promising novel safe checkpoint inhibitor vaccine.
A Prospective Study Regarding the Efficacy and Safety of the BNT162b2 Vaccine in Patients With Solid Malignancies Undergoing Systemic Chemotherapy. [2022]To prospectively evaluate the efficacy and safety of the BNT162b2 vaccine in solid cancer patients undergoing systemic chemotherapy (n=63).
Therapeutic cancer vaccines. [2007]Therapeutic cancer vaccines target the cellular arm of the immune system to initiate a cytotoxic T-lymphocyte response against tumor-associated antigens. Immunotherapy offers one of the few therapeutic options that reproducibly leads to a subset of patients with long-term remissions (seemingly cures) of widely metastatic disease. Therapeutic cancer vaccines tested in clinical trials have included inactivated tumor cells administered in immunological adjuvants or after genetic modification to increase their immunogenicity. Other forms are heat shock protein vaccines and anti-ganglioside antibodies. Tumor-associated antigenic peptides have been fully characterized for some cancers. Finally, strategies to directly expand antitumor T lymphocytes and adoptively transfer them to patients with cancer have been developed and shown to induce objective tumor regressions.
Therapeutic vaccination with tumor cells that engage CD137. [2018]Therapeutic cancer vaccination is based on the finding that tumors in both humans and experimental animals, such as mice, express potential immunological targets, some of which have high selectivity for cancer cells. In contrast to the successful vaccination against some infectious diseases, where most vaccines induce neutralizing antibodies that act prophylactically, the aim of therapeutic cancer vaccines is to treat established tumors (primarily micrometastases). Since most tumor-destructive immune responses are cell-mediated, therapeutic cancer vaccination needs to induce and expand such responses and also to overcome "escape" mechanisms that allow tumors to evade immunological destruction. Tumor antigens (as with other antigens) are presented by "professional" antigen-presenting cells, most notably dendritic cells (DC). Therefore DC that have been transfected or "pulsed" to present antigen provide a logical source of tumor vaccines, and some encouraging results have been obtained clinically as well as in preclinical models. An alternative and more physiological approach is to develop vaccines that deliver tumor antigen for in vivo uptake and presentation by the DC. Vaccines of the latter type include tumor cells that have been modified to produce certain lymphokines or express costimulatory molecules, as well as cDNAs, recombinant viruses, proteins, peptides and glycolipids which are often given together with an adjuvant. Several studies over the past 5 years have demonstrated dramatic therapeutic responses against established mouse tumors as a result of repeated injections of agonistic monoclonal antibodies (MAbs) to the costimulatory molecule CD137 (4-1BB). However, the clinical use of such MAbs may be problematic since they depress antibody formation, for example, to infectious agents. The alternative approach to transfect tumor cells to express the CD137 ligand (CD137L) increases their immunogenicity, but vaccination with tumor cells expressing CD137L is ineffective in several systems where injection of anti-CD137 MAb produces tumor regression. Recent findings indicate that a more effective way to engage CD137 towards tumor destruction is to transfect tumor cells to express a cell-bound form of anti-CD137 single-chain Fv fragments (scFv). Notably, tumors from melanoma K1735, growing either subcutaneously or in the lung, could be eradicated following vaccination with K1735 cells that expressed anti-CD137 scFv. This was in spite of the fact that K1735, as with many human neoplasms, expresses very low levels of MHC class I and has low immunogenicity. Similar results were subsequently obtained with other tumors of low immunogenicity, including sarcoma Ag104. We hypothesize that the concomitant expression of tumor antigen and anti-CD137 scFv effectively engages NK cells, monocytes and dendritic cells, as well as activated CD4(+) and CD8(+) T cells (all of which express CD137) so as to induce and expand a tumor-destructive Th1 response. While vaccines in the form of transfected tumor cells can be effective, at least in mouse models, the logical next step is to construct vaccines that combine genes that encode molecularly defined tumor antigens with a gene that encodes anti-CD137 scFv. Before planning any clinical trials, vaccines that engage CD137 via scFv need to be compared in demanding mouse models for efficacy and side effects with vaccines that are already being tested clinically, including transfected DC and tumor cells producing granulocyte-macrophage colony-stimulating factor.