ACTM-838 for Cancer

Recruiting at 1 trial location

Overseen By Shouryadeep 'Deep' Senior VP, Clinical Development, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Actym Therapeutics, Inc.

Must not be taking: Corticosteroids, Immunosuppressives

Disqualifiers: Autoimmune disease, Brain metastases, others

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

Compensation: Varies

Number of Visits: Unknown

35 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a first in human (FIH) 2-part study using ACTM-838 in patients with advanced solid tumors resistant to standard of care treatment. Part 1a will evaluate dose escalation and Part 1b will evaluate dose expansion.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment ACTM-838 for cancer?

The research suggests that improvements in progression-free survival (PFS) and time to progression (TTP) in cancer treatments are strongly linked to better overall survival, which could imply that ACTM-838 might be effective if it shows similar improvements in PFS or TTP. ^{1 2 3 4 5}

What safety data exists for ACTM-838 or similar treatments?

The research mentions MK886, a similar treatment, which has low toxicity in animal studies, suggesting it might be safe for humans. However, Actinomycin D, another related treatment, has a known toxicity profile, especially affecting neurons, indicating potential safety concerns. ^{6 7 8 9 10}

How is the treatment ACTM-838 different from other cancer treatments?

ACTM-838 is unique because it involves adoptive cell transfer (ACT) using CD8+ T-cells that are specifically stimulated with an anti-OX40 antibody, enhancing their ability to fight cancer by promoting long-term memory and persistence, which is not a feature of traditional chemotherapy or radiation treatments. ^{11 12 13 14 15}

Research Team

SVP, Clinical Development, MD, PhD

Principal Investigator

Actym Therapeutics, Inc.

Eligibility Criteria

This trial is for adults with advanced solid tumors that no longer respond to standard treatments. Participants must be in good physical condition (ECOG 0-1), have a CD4 count over 500/mL, at least one tumor visible on CT or MRI scans that can be biopsied, and their blood, liver, and heart functions should meet specific medical standards.

Inclusion Criteria

I have an advanced cancer with no standard treatment options left.

I am fully active or can carry out light work.

I have a tumor that can be measured and biopsied, visible on CT or MRI scans.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Part 1a evaluates the safety, tolerability, and activity of escalating doses of ACTM-838 to estimate the maximum tolerated dose and/or the optimum biological dose as a monotherapy

8-12 weeks

Dose Expansion

Part 1b further evaluates ACTM-838 in patients with advanced specific tumor types at the recommended dose determined in Part 1a

12-16 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• ACTM-838

Trial Overview ACTM-838 is being tested in this study. The first part of the trial will find the right dose of ACTM-838. Once the dose is determined, more people will join the second part to see how well it works at that dose against various solid tumors.

Participant Groups

Group I: ACTM-838 Monotherapy Experimental Treatment 1 Intervention

Escalating doses of ACTM-838 in Part 1a followed by expansion in Part 1b at the recommended dose determined in Part 1a

Who Is Running the Clinical Trial?

Actym Therapeutics, Inc.

Lead Sponsor

Trials

1

Recruited

40+

Findings from Research

In a review of 36 randomized trials involving 10,484 patients with advanced gastric cancer, progression-free survival (PFS) and time to progression (TTP) were found to strongly correlate with overall survival (OS), suggesting they could serve as reliable indicators of treatment effectiveness.

The study revealed a higher correlation for PFS compared to TTP, particularly in trials conducted outside Asia and those involving patients with measurable lesions, indicating that PFS may be a more effective endpoint for evaluating new chemotherapy agents in future trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Progression-free survival and time to progression as surrogate markers of overall survival in patients with advanced gastric cancer: analysis of 36 randomized trials. Shitara, K., Ikeda, J., Yokota, T., et al.[2021]

The IePRO model of care utilizes electronic patient-reported outcome (ePRO) data to actively monitor and manage symptoms in patients receiving immune checkpoint inhibitors, aiming to improve quality of care and patient outcomes.

This model is currently being evaluated in a randomized controlled trial, demonstrating a structured workflow where triage nurses respond to patient-reported symptoms, facilitating timely interventions and enhancing collaboration among care teams.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of an eHealth-enhanced model of care for the monitoring and management of immune-related adverse events in patients treated with immune checkpoint inhibitors. da Silva Lopes, AM., Colomer-Lahiguera, S., Darnac, C., et al.[2023]

Phase II trials traditionally rely on tumor shrinkage as a measure of effectiveness, but recent findings suggest that some targeted therapies may still provide survival benefits even with low response rates, highlighting the need for better evaluation methods.

The review discusses the exploration of alternative endpoints for phase II trials, such as progression-free survival and continuous tumor size measurement, which may help identify effective treatments without prematurely halting promising agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alternate endpoints for screening phase II studies. Dhani, N., Tu, D., Sargent, DJ., et al.[2022]

Integrating patient-reported outcomes (PROs) into oncology practice can enhance clinical care by improving symptom monitoring and reducing the need for acute care, ultimately benefiting patient well-being.

Despite challenges such as costs and potential physician burnout, the systematic use of PROs offers significant advantages for personalized clinical decision-making and patient-centered research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Translation of Patient-Reported Outcomes in Oncology Clinical Trials to Everyday Practice. Ivatury, SJ., Hazard-Jenkins, HW., Brooks, GA., et al.[2023]

Daily electronic patient-reported outcomes (ePROs) significantly improved symptom management for 217 cancer patients undergoing treatment, with over 50% of assessments generating alerts for moderate to severe symptoms.

The study found that red alerts (indicating severe symptoms) were often detected without prior warnings, and these alerts were linked to a higher likelihood of acute care visits, highlighting the importance of regular monitoring in improving patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of a Remote Monitoring Program for Symptoms Among Adults With Cancer Receiving Antineoplastic Therapy. Daly, B., Nicholas, K., Flynn, J., et al.[2022]

MK886, a small molecular inhibitor, shows promising antitumor activity by down-regulating actin B and disrupting the cytoskeleton in cancer cells, which may enhance the effects of treatments like UV radiation.

The low toxicity of MK886 in vivo suggests it could be safely used in humans, and its interaction with dietary lipids indicates potential for a targeted delivery system using liposomes to improve treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ingenuity network-assisted transcription profiling: Identification of a new pharmacologic mechanism for MK886. Mayburd, AL., Martlínez, A., Sackett, D., et al.[2022]

Actinomycin D (ActD) effectively inhibits the growth of various aerodigestive tract cancer cell lines and induces apoptosis, with IC50 values ranging from 0.021 to 2.96 nM, indicating its potential as a powerful anticancer agent.

The mechanism of action involves the activation of the p53 signaling pathway, particularly through the p53-p21 pathway, which is crucial for the apoptosis induced by low-dose ActD, supporting its use in combination therapies to enhance efficacy while potentially reducing toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Context-dependent activation of p53 target genes and induction of apoptosis by actinomycin D in aerodigestive tract cancers. Adeluola, AA., Bosomtwe, N., Long, TE., et al.[2023]

Actein (ACT) enhances the effectiveness of TRAIL therapy in gastric cancer cells, making them more sensitive to TRAIL-induced apoptosis by altering key apoptotic proteins and increasing decoy receptors, which are dependent on the p53 pathway.

In a mouse model, the combination of ACT and TRAIL significantly inhibited gastric cancer growth compared to either treatment alone, demonstrating a promising therapeutic strategy with no observed toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Actein enhances TRAIL effects on suppressing gastric cancer progression by activating p53/Caspase-3 signaling. Yang, ZC., Ma, J.[2018]

Actinomycin D (ActD) can stabilize and activate the tumor suppressor protein p53 through two mechanisms: blocking transcription at high concentrations and inducing ribosomal stress at low concentrations, making it a candidate for p53-based cancer therapy.

The study found that the activation of p53 by ActD is mediated through the PI3K/AKT signaling pathway, as inhibitors of this pathway significantly reduced p53 expression, highlighting a specific mechanism of action that could be targeted in cancer treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AKT mediates actinomycin D-induced p53 expression. Chen, CS., Ho, DR., Chen, FY., et al.[2021]

Actinomycin D (ActD) shows promise as a treatment for glioblastoma by significantly reducing tumor growth and increasing survival in mouse models, primarily by downregulating SOX2 expression.

However, ActD poses a risk of direct toxicity to primary cortical neurons, with findings indicating poor reversibility of transcription activity even after short exposures, highlighting the need for careful consideration of neurological side effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Survival and functional recovery of primary cortical neurons exposed to actinomycin D. Lee, SE., Lee, GH.[2022]

Adoptive cell transfer (ACT) using OX40-driven tumor-specific CD8+ T-cells showed enhanced early differentiation and anti-apoptotic properties, which may improve their effectiveness in targeting tumors.

These OX40-driven T-cells not only proliferated effectively in tumor-bearing mice but also established long-term memory, suggesting a promising strategy for enhancing the efficacy of cancer immunotherapy with reduced toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vivo antitumor function of tumor antigen-specific CTLs generated in the presence of OX40 co-stimulation in vitro. Pham Minh, N., Murata, S., Kitamura, N., et al.[2018]

Cancer immunotherapy, particularly adoptive CD8+ T cell therapy (ACT), harnesses the body's immune system to target tumors, offering potential long-term protection with less toxicity compared to traditional treatments like chemotherapy and radiation.

The most successful form of ACT, anti-CD19 CAR-T cell therapy, has shown efficacy in treating B cell lymphoma and is already approved, although achieving similar success in solid tumors remains a challenge.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adoptive CD8+ T cell therapy against cancer:Challenges and opportunities. Jiang, X., Xu, J., Liu, M., et al.[2020]

Dual immunotherapy using aOX40 and aCTLA-4 significantly enhances CD8 T-cell responses, leading to improved survival in a mammary carcinoma model, indicating its potential as a powerful cancer treatment.

The combination therapy not only boosts the effectiveness of T-cells against tumors but also limits the production of certain cytokines that could hinder the immune response, showcasing a refined approach to cancer immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination OX40 agonism/CTLA-4 blockade with HER2 vaccination reverses T-cell anergy and promotes survival in tumor-bearing mice. Linch, SN., Kasiewicz, MJ., McNamara, MJ., et al.[2021]

Adoptive cell transfer (ACT) is an innovative immunotherapy that involves isolating and enhancing a patient's own immune cells to better target and fight cancer, with ongoing improvements making the process safer and more effective.

Recent developments in ACT have led to an increase in clinical trials aimed at evaluating its safety and effectiveness in treating various cancers, highlighting its growing importance in cancer treatment research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trial Watch: Adoptive cell transfer for anticancer immunotherapy. Aranda, F., Vacchelli, E., Obrist, F., et al.[2021]

In a mouse model of human gastric cancer, the use of ACTIL-15 lymphocytes significantly inhibited tumor growth and improved survival rates compared to other treatments, indicating strong antitumor potential.

In a clinical trial with 63 patients suffering from advanced gastric cancer, combining ACTIL-15 lymphocytes with standard chemotherapy resulted in a median survival of 472 days, compared to 266 days for those receiving chemotherapy alone, demonstrating enhanced efficacy with an acceptable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IL-15-induced lymphocytes as adjuvant cellular immunotherapy for gastric cancer. Hu, Y., Liu, D., Cui, P., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Progression-free survival and time to progression as surrogate markers of overall survival in patients with advanced gastric cancer: analysis of 36 randomized trials. [2021]

2. Germany pubmed.ncbi.nlm.nih.gov

Development of an eHealth-enhanced model of care for the monitoring and management of immune-related adverse events in patients treated with immune checkpoint inhibitors. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Alternate endpoints for screening phase II studies. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Translation of Patient-Reported Outcomes in Oncology Clinical Trials to Everyday Practice. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Analysis of a Remote Monitoring Program for Symptoms Among Adults With Cancer Receiving Antineoplastic Therapy. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Ingenuity network-assisted transcription profiling: Identification of a new pharmacologic mechanism for MK886. [2022]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Context-dependent activation of p53 target genes and induction of apoptosis by actinomycin D in aerodigestive tract cancers. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Actein enhances TRAIL effects on suppressing gastric cancer progression by activating p53/Caspase-3 signaling. [2018]

9. United States pubmed.ncbi.nlm.nih.gov

AKT mediates actinomycin D-induced p53 expression. [2021]

10. United States pubmed.ncbi.nlm.nih.gov

Survival and functional recovery of primary cortical neurons exposed to actinomycin D. [2022]

11. United States pubmed.ncbi.nlm.nih.gov

In vivo antitumor function of tumor antigen-specific CTLs generated in the presence of OX40 co-stimulation in vitro. [2018]

12. Ireland pubmed.ncbi.nlm.nih.gov

Adoptive CD8+ T cell therapy against cancer:Challenges and opportunities. [2020]

13. United States pubmed.ncbi.nlm.nih.gov

Combination OX40 agonism/CTLA-4 blockade with HER2 vaccination reverses T-cell anergy and promotes survival in tumor-bearing mice. [2021]

14. United States pubmed.ncbi.nlm.nih.gov

Trial Watch: Adoptive cell transfer for anticancer immunotherapy. [2021]

15. United States pubmed.ncbi.nlm.nih.gov

IL-15-induced lymphocytes as adjuvant cellular immunotherapy for gastric cancer. [2022]