Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Immuneering Corporation
Disqualifiers: CNS metastases, Cardiac disease, Diabetes, RVO, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This is a FIH, ascending dose study to characterize the safety, tolerability, optimal dose and preliminary anti-tumor activity of IMM-6-415 in participants with advanced or metastatic solid tumors harboring RAS or RAF oncogenic mutations.
Will I have to stop taking my current medications?
The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor.
What data supports the effectiveness of the drug IMM-6-415 for solid tumors?
The research suggests that targeting oncostatin M (OSM), a molecule involved in cancer growth and spread, could help reduce aggressive cancer behavior and therapy failure, which might be relevant to the effectiveness of IMM-6-415 if it targets similar pathways.
12345What safety data exists for the treatment IMM-6-415 in humans?
AMG 232, which may be related to IMM-6-415, was tested in a study with patients having advanced solid tumors or multiple myeloma. It was generally safe up to a dose of 240 mg, with some patients experiencing mild to moderate side effects like diarrhea, nausea, and fatigue. Serious side effects included low platelet counts (thrombocytopenia) and low white blood cell counts (neutropenia).
678910Eligibility Criteria
This trial is for adults with advanced or metastatic solid tumors, like melanoma and lung cancer, that have specific genetic changes called RAS or RAF mutations. Participants should not have had prior treatment with IMM-6-415.Inclusion Criteria
My cancer is advanced, cannot be surgically removed, and has specific RAS or RAF mutations.
I have been treated with a KRASG12C inhibitor for my condition.
My scans show at least one measurable tumor.
I am fully active or can carry out light work.
I am 18 years old or older.
My cancer is one of the specified types and has certain genetic mutations.
I have been treated with KRAS inhibitors before.
Exclusion Criteria
I have heart problems that affect my daily activities.
I had severe COVID-19 and now need extra oxygen to keep my oxygen levels above 90%.
I have side effects from cancer treatment that are still bothersome.
I have a history of serious eye conditions or am at risk for retinal vein blockage.
I am not pregnant, breastfeeding, nor planning to become pregnant, and I do not plan to father a child while in this study.
I need frequent drainage for fluid buildup in my chest or abdomen more than once a month. I may have a permanent drainage tube.
I cannot swallow pills.
I have brain metastases that are untreated or getting worse.
I have not had rhabdomyolysis in the last 3 months.
Participant Groups
The study tests a new drug named IMM-6-415 to find the safest dose and see how well it works against certain cancers. It's an early-stage trial where doses increase gradually to monitor effects on patients' tumors.
1Treatment groups
Experimental Treatment
Group I: IMM-6-415Experimental Treatment1 Intervention
Dose Escalation and Dose Expansion
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Sarah Cannon Research InstituteDenver, CO
Massachusetts General HospitalBoston, MA
Honor Health Research InstituteScottsdale, AZ
City of HopeDuarte, CA
More Trial Locations
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Who is running the clinical trial?
Immuneering CorporationLead Sponsor
References
Breaking the oncostatin M feed-forward loop to suppress metastasis and therapy failure. [2019]Deciphering the complex milieu that makes up the tumor microenvironment (TME) and the signaling engaged by TME cytokines continues to provide novel targets for therapeutic intervention. The IL-6 family member oncostatin M (OSM) has recently emerged as a potent driver of tumorigenesis, metastasis, and therapy failure, molecular programs most frequently attributed to IL-6 itself. In a recent issue of The Journal of Pathology, Kucia-Tran et al describe how elevated oncostatin M receptor (OSMR) expression results in a feed-forward loop involving the de novo production of both OSM and OSMR to facilitate aggressive properties in squamous cell carcinoma (SCC). Here, we discuss how new findings implicating OSM in conferring aggressive cancer cell properties can be leveraged to suppress metastatic outgrowth and therapy failure in SCC as well as other cancers. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Prognostic Value of Programmed Cell Death 1 Ligand-1 in Patients With Bone and Soft Tissue Sarcomas: A Systemic and Comprehensive Meta-Analysis Based on 3,680 Patients. [2020]Background: Programmed cell death 1 ligand-1 (PD-L1) is an immune checkpoint molecule that acts to protect cancer cells from immune surveillance and is considered as a prognostic biomarker in several cancers, but the prognostic value of PD-L1 in bone and soft tissue sarcomas remains inconclusive. In the present meta-analysis, the clinicopathological and prognostic value of PD-L1 in sarcomas was evaluated. Method: We performed a systemic and comprehensive meta-analysis by searching the PubMed, Medline, Cochrane Library, EMBASE, and Web of Science databases up to October 31, 2019. Eligible articles were incorporated, and pooled hazard ratios (HRs) and odds ratios (ORs) with their 95% confidence intervals (CIs) were used to estimate the outcomes. Results: Thirty-six articles containing 39 independent studies with 3,680 bone and soft tissue sarcoma patients were included in our meta-analysis. The pooled results showed that PD-L1 overexpression could predict poor overall survival (HR 1.45, 95% CI 1.11-1.90, P < 0.01), metastasis-free survival (HR 1.58, 95% CI 1.14-2.19, P < 0.01), and event-free survival (HR 2.82, 95% CI 1.69-4.71, P < 0.01) in sarcomas. Furthermore, PD-L1 overexpression was correlated with a higher rate of tumor metastasis (OR 2.95, 95% CI 1.32-6.60, P < 0.01), a more advanced tumor grade (OR 3.63, 95% CI 2.55-5.16, P < 0.01), and more T lymphocyte infiltration (OR 5.55, 95% CI 2.86-10.76, P < 0.01). No obvious publication bias was observed, and the sensitivity analysis showed that our results were robust. Conclusion: The results of our meta-analysis indicate that high PD-L1 expression might serve as a valuable and predictive biomarker for adverse clinicopathological features and poor prognosis in patients with sarcoma.
PD-L1 Expression in Colorectal Carcinoma: A Comparison of 3 Scoring Methods in a Cohort of Jordanian Patients. [2023]Anti-programmed death-ligand 1 (PD-L1) treatments can improve colorectal carcinoma (CRC) survival; however, there is still controversy regarding the relationship between PD-L1 expression and the outcome of immunotherapeutic treatment and survival. The discrepancies are partly caused by the lack of a unified scoring system. This retrospective, cross-sectional study evaluated PD-L1 by immunohistochemistry in 127 CRC cases and compared the 3 scoring systems used to assess PD-L1: Tumor Percentage Score (TPS), Combined Positive Score (CPS), and immune cell (IC) score. Correlations were calculated using the χ 2 test. Kaplan-Meier curves with the Log-rank test were used to measure the contribution of PD-L1 expression to survival. PD-L1-positive rate were 29.9%, 57.5%, and 55.9% based on TPS, CPS, and IC score, respectively. TPS showed a better correlation with the clinicopathologic features being significantly higher with young age, T4, and adenocarcinomas (compared with mucinous/signet ring). TPS also showed an increasing trend with higher grade, lymph node stage, and male sex, although these variables were not significantly associated with PD-L1 expression. There was no correlation between PD-L1 expression and mismatch repair protein status in the 3 scoring methods. The probability of survival was higher for PD-L1-negative cases in the first 60 months after surgery if scored by the TPS method ( P =0.058). Future efforts correlating PD-L1 status with response to treatment are needed to decide on the best scoring method to be used for making therapy decisions.
A pan-cancer analysis of PD-L1 immunohistochemistry and gene amplification, tumor mutation burden and microsatellite instability in 48,782 cases. [2023]PD-L1 immunohistochemistry (IHC) currently has the most Food and Drug Administration (FDA) approvals as a companion diagnostic (CDx) for immunotherapies in specific tumor types; however, multiple other immunotherapy biomarkers exist. We performed this study to examine and report the prevalence of PD-L1 expression in a wide variety of tumor types and examine its relationship to microsatellite instability (MSI), tumor mutational burden (TMB), and CD274 (PD-L1) gene amplification. We performed a retrospective analysis of all cases in which both PD-L1 IHC (using the DAKO 22C3 IHC assay with either tumor proportion score (TPS) or combined positive score (CPS); or the VENTANA SP142 assay with infiltrating immune cell score (IC)) and comprehensive genomic profiling (CGP) were tested at Foundation Medicine between January 2016 and November 2019. Of note, PD-L1 positivity is defined per the CDx indication and tumor proportion score (TPS ≥ 1) for indications without a CDx claim; and TMB positivity is defined as ≥10 mutations/Mb. A total of 48,782 cases were tested for PD-L1 IHC and CGP. Immune cell expression of PD-L1 was more frequently identified than tumor cell expression of PD-L1. We saw a high correlation between PD-L1 expression and CD274 gene amplification (p < 0.0001), MSI and TMB (p < 0.0001), and PD-L1 and TMB (p < 0.0001). In addition, the combination of PD-L1 and TMB identified four unique disease subsets PD-L1-/TMB-, PD-L1+/TMB-, PD-L1-/TMB+, and PD-L1+/TMB+ with varying prevalence dependent on tumor type. Lastly, 50.3% (24527/48782) of the overall cohort was positive for at least one of the CDx or exploratory biomarkers described above. This is the largest pan-cancer analysis of relevant biomarkers associated with response to checkpoint inhibitors to date, including more than 48,000 cases. Additional clinical trials with treatment outcome data in individual tumor types are needed to determine whether the double positive PD-L1+/TMB+ disease subset would respond best to immunotherapy.
Impact of PD-L1 Scores and Changes on Clinical Outcome in Rectal Cancer Patients Undergoing Neoadjuvant Chemoradiotherapy. [2020]Reports on the prognostic role of programmed death-ligand 1 (PD-L1) expression in rectal cancer are controversial. We investigated expression patterns and changes of PD-L1 in rectal cancer patients undergoing neoadjuvant chemoradiotherapy (CRT). Seventy-two patients diagnosed with rectal cancer and/or treated with fluorouracil-based neoadjuvant CRT at the Department of Internal Medicine III of the Paracelsus Medical University Salzburg (Austria) between January 2003 and October 2012 were included. PD-L1 scoring was performed according to the tumor proportion score (TPS), combined positive score (CPS), and immune cell score (IC). PD-L1 TPS prior to neoadjuvant CRT had a statistically significant impact on survival (median: ≤1%: 95.4 months (95% CI: 51.8-not reached) vs. >1%: not reached, p = 0.03, log-rank). Patients with a PD-L1 TPS ≤1% prior to and after CRT showed an inferior survival compared to all other patients (median: 56.7 months (95% CI: 51.4-not reached) vs. not reached, p = 0.005, log-rank). In multivariate analysis, PD-L1 TPS prior to neoadjuvant CRT (>1% vs. ≤1%, hazard ratio: 0.29 (95% CI: 0.11-0.76), p = 0.01) remained independently associated with survival. In conclusion, low PD-L1 TPS was associated with inferior survival in rectal cancer patients undergoing neoadjuvant CRT. A prospective validation of the prognostic value of PD-L1 expression in rectal cancer patients within a clinical trial is necessitated.
AMG-232, a New Inhibitor of MDM-2, Enhance Doxorubicin Efficiency in Pre-B Acute Lymphoblastic Leukemia Cells. [2023]Doxorubicin (DOX)-induced cardiotoxicity appears to be a growing concern for extensive use in acute lymphoblastic leukemia (ALL). The new combination treatment strategies, therefore might be an effective way of decreasing its side effects as well as improving efficacy. AMG232 (KRT-232) is a potential MDM-2 inhibitor, increasing available p53 through disturbing p53-MDM-2 interaction. In this study, we examined the effects of AMG232 on DOX-induced apoptosis of NALM-6 cells.
Phase 1 study of the MDM2 inhibitor AMG 232 in patients with advanced P53 wild-type solid tumors or multiple myeloma. [2022]Background This open-label, first-in-human, phase 1 study evaluated AMG 232, an oral selective MDM2 inhibitor in patients with TP53 wild-type (P53WT), advanced solid tumors or multiple myeloma (MM). Methods In the dose escalation (n = 39), patients with P53WT refractory solid tumors enrolled to receive once-daily AMG 232 (15, 30, 60, 120, 240, 480, and 960 mg) for seven days every 3 weeks (Q3W). In the dose expansion (n = 68), patients with MDM2-amplified (well-differentiated and de-differentiated liposarcomas [WDLPS and DDLPS], glioblastoma multiforme [GBM], or other solid tumors [OST]), MDM2-overexpressing ER+ breast cancer (BC), or MM received AMG 232 at the maximum tolerated dose (MTD). Safety, pharmacokinetics, pharmacodynamics, and efficacy were assessed. Results AMG 232 had acceptable safety up to up to 240 mg. Three patients had dose-limiting toxicities of thrombocytopenia (n = 2) and neutropenia (n = 1). Due to these and other delayed cytopenias, AMG 232 240 mg Q3W was determined as the highest tolerable dose assessed in the dose expansion. Adverse events were typically mild/moderate and included diarrhea, nausea, vomiting, fatigue, decreased appetite, and anemia. AMG 232 plasma concentrations increased dose proportionally. Increases in serum macrophage inhibitor cytokine-1 from baseline were generally dose dependent, indicating p53 pathway activation. Per local review, there were no responses. Stable disease (durability in months) was observed in patients with WDLPS (3.9), OST (3.3), DDLPS (2.0), GBM (1.8), and BC (1.4-2.0). Conclusions In patients with P53WT advanced solid tumors or MM, AMG 232 showed acceptable safety and dose-proportional pharmacokinetics, and stable disease was observed.
The MDM2-p53 Antagonist Brigimadlin (BI 907828) in Patients with Advanced or Metastatic Solid Tumors: Results of a Phase Ia, First-in-Human, Dose-Escalation Study. [2023]Brigimadlin (BI 907828) is an oral MDM2-p53 antagonist that has shown encouraging antitumor activity in vivo. We present phase Ia results from an open-label, first-in-human, phase Ia/Ib study investigating brigimadlin in patients with advanced solid tumors (NCT03449381). Fifty-four patients received escalating doses of brigimadlin on day 1 of 21-day cycles (D1q3w) or days 1 and 8 of 28-day cycles (D1D8q4w). Based on dose-limiting toxicities during cycle 1, the maximum tolerated dose was selected as 60 mg for D1q3w and 45 mg for D1D8q4w. The most common treatment-related adverse events (TRAE) were nausea (74.1%) and vomiting (51.9%); the most common grade ≥3 TRAEs were thrombocytopenia (25.9%) and neutropenia (24.1%). As evidence of target engagement, time- and dose-dependent increases in growth differentiation factor 15 levels were seen. Preliminary efficacy was encouraging (11.1% overall response and 74.1% disease control rates), particularly in patients with well-differentiated or dedifferentiated liposarcoma (100% and 75% disease control rates, respectively).
Ombrabulin plus cisplatin versus placebo plus cisplatin in patients with advanced soft-tissue sarcomas after failure of anthracycline and ifosfamide chemotherapy: a randomised, double-blind, placebo-controlled, phase 3 trial. [2018]Ombrabulin (AVE8062) disrupts the vasculature of established tumours and has shown preclinical synergistic anti-tumour activity when combined with cisplatin. In this phase 3 trial, we aimed to assess the efficacy and safety of ombrabulin plus cisplatin compared with placebo plus cisplatin in patients with advanced soft-tissue sarcomas.
[Studies on antitumor activities and pulmonary toxicity of pepleomycin sulfate (NK631) (author's transl)]. [2016]The antimicrobial and antitumor activities, and the pulmonary toxicity of pepleomycin (NK631) were studied in comparison with bleomycin (BLM). NK631 showed a broad antimicrobial spectrum against gram positive and gram negative bacteria equally to BLM, and its activity was about twice higher than BLM. NK631 showed higher activity on cultured HeLa S3 cells and higher antitumor effect on the transplanted tumors of Ehrlich solid carcinoma in mice, AH66 and AH66F ascites hepatoma in rats, and lower antitumor effect on Ehrlich ascites carcinoma in mice than BLM. Similarly to BLM, NK631 did not show satisfactory activity on L1210 leukemia in mice. NK631 showed marked effect on chemically induced squamous cell carcinoma, spontaneous lymph sarcoma of a dog, human and dog gastric cancer heterotransplanted in nude mice equally to BLM. Furthermore NK631 exhibited remarkably higher antitumor activity on lymph node metastasis of AH66 ascites hepatoma of rats and chemically induced gastric carcinoma of rats than BLM. Pulmonary toxicity of NK631 was low as 1/3 in incidence and 1/4 in grade of the BLM in old mice system. This trend was confirmed by chemical analysis of hydroxyproline in lung.