CoREST Inhibitor + Anti-PD-1 Therapy for Solid Cancers

Recruiting at 13 trial locations

Overseen By Tiffany Wang, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Tango Therapeutics, Inc.

Disqualifiers: Active infection, Active malignancy, CNS metastases, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

126 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of treatments for individuals with advanced solid tumors, particularly those with an STK11 mutation. Researchers aim to determine the best dose for the next phase, assess safety and tolerance, and understand how the body processes the new drug, TNG260 (a CoREST inhibitor). The trial targets those with an STK11 mutation in tumors such as pancreatic, breast, or lung cancer. Participants will receive TNG260 with pembrolizumab (an anti-PD-1 therapy) until they experience side effects, the disease progresses, or they choose to stop. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new therapy.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that TNG260, when combined with pembrolizumab, is still under careful study to ensure safety for people. Early studies of this combination aim to determine the best dose and assess tolerability. Pembrolizumab has FDA approval for treating certain cancers, indicating its well-established safety. However, TNG260 is newer, so its safety profile is less understood.

As this trial is in the early stages, it focuses on evaluating the treatment's safety and tolerability. Researchers closely monitor for any side effects. Participants will continue receiving the treatment unless they experience significant side effects or choose to stop.

This early phase trial is crucial for understanding the safety of TNG260 when used with pembrolizumab. It represents an essential step before broader testing in later stages. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of CoREST inhibitor TNG260 and pembrolizumab for treating solid tumors because it offers a novel approach compared to standard options like chemotherapy and targeted therapies. Most treatments for STK11-mutant tumors focus on inhibiting cancer growth through traditional pathways, but TNG260 works differently by targeting the CoREST complex, potentially enhancing the immune response. This combination with pembrolizumab, an anti-PD-1 therapy that helps the immune system recognize and attack cancer cells, could improve outcomes for patients with these challenging mutations. By addressing these genetic mutations specifically, this approach may provide a more effective treatment option for patients with advanced or metastatic solid tumors.

What evidence suggests that this trial's treatments could be effective for advanced solid tumors with an STK11 mutation?

Research shows that TNG260, a new drug, may work well with pembrolizumab to treat advanced solid tumors with an STK11 mutation. Early lab studies indicate that TNG260 helps the immune system find and attack cancer cells by altering the tumor's environment. This trial includes several arms where participants receive TNG260 with pembrolizumab. This combination aims to prevent tumors from evading the body's defenses. Initial studies in a type of lung cancer with STK11 mutations suggested this method could enhance the effectiveness of pembrolizumab, a cancer treatment. While more research is needed, these findings suggest a promising approach for these difficult-to-treat cancers. ^{2 3 4 6 7}

Who Is on the Research Team?

Adam Crystal, MD, PhD

Principal Investigator

Tango Therapeutics, Inc.

Are You a Good Fit for This Trial?

Adults with advanced solid tumors and a specific genetic change called STK11 mutation can join this trial. They should have good organ function, no current severe illnesses or other cancers, not be pregnant, and able to consent. The trial is for those who haven't had success with other treatments and are in fairly good physical condition.

Inclusion Criteria

My liver is working well according to recent tests.

My organs are working well according to recent tests.

Has measurable disease based on RECIST v1.1

Exclusion Criteria

Currently participating in or has planned participation in a study of another investigational agent or device

I am currently pregnant or breastfeeding.

I am not allergic to TNG260, PD-1 antibody, or its ingredients.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive escalating doses of TNG260 in combination with pembrolizumab to estimate the maximum tolerated dose (MTD)

6 weeks

Weekly visits for dose escalation

Dose Expansion

Participants receive TNG260 at the recommended phase 2 dose (RP2D) in combination with pembrolizumab

12 weeks

Bi-weekly visits for treatment monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Pembrolizumab
• TNG260

Trial Overview

The study tests TNG260 combined with pembrolizumab in patients whose tumors have the STK11 mutation. It aims to find the right dose for future studies, check safety and how well it's tolerated, understand how the body processes TNG260, and see if it helps against cancer.

How Is the Trial Designed?

Group I: Dose Expansion in NSCLC with KRAS Wild type Experimental Treatment 2 Interventions

Participants with STK11-mutant and KRAS-wild type NSCLC (squamous and non-squamous) will receive TNG260 at the identified RP2D in combination with pembrolizumab

Group II: Dose Expansion in NSCLC with KRAS Mutation Experimental Treatment 2 Interventions

Participants with STK11-mutant and KRAS-mutant NSCLC (squamous and non squamous) will receive TNG260 at the identified RP2D in combination with pembrolizumab

Group III: Dose Expansion in Advanced or Metastatic Solid Tumors Experimental Treatment 2 Interventions

Participants with STK11-mutant solid tumors (including but not limited to pancreatic, endometrial, cervical, breast, and carcinoma of unknown primary) will receive TNG260 at the identified RP2D in combination with pembrolizumab

Group IV: Dose Escalation Experimental Treatment 2 Interventions

Participants with STK11-mutant solid tumors will receive escalating doses of TNG260 in combination with pembrolizumab to estimate the MTD

Pembrolizumab is already approved in United States, European Union, United Kingdom for the following indications:

Approved in United States as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in European Union as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in United Kingdom as KEYTRUDA for:

• Untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1

Who Is Running the Clinical Trial?

Tango Therapeutics, Inc.

Lead Sponsor

Trials

5

Recruited

740+

Published Research Related to This Trial

In a phase Ib trial involving 26 patients with advanced PD-L1-positive ovarian cancer, pembrolizumab demonstrated a confirmed objective response rate of 11.5%, indicating some level of antitumor activity, with 1 complete response and 2 partial responses observed.

The treatment was generally well-tolerated, with 73.1% of patients experiencing treatment-related adverse events, but no deaths or treatment discontinuations due to these events, suggesting that pembrolizumab has a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in patients with programmed death ligand 1-positive advanced ovarian cancer: Analysis of KEYNOTE-028. Varga, A., Piha-Paul, S., Ott, PA., et al.[2019]

Pembrolizumab (Keytruda) effectively blocks the PD-1 pathway, enhancing T-cell activity against tumors, which supports its role in promoting tumor regression and immune rejection.

Preclinical studies in cynomolgus monkeys showed that pembrolizumab has a favorable safety profile with no significant toxicological findings, aligning with its demonstrated safety and efficacy in human clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biophysical and Immunological Characterization and In Vivo Pharmacokinetics and Toxicology in Nonhuman Primates of the Anti-PD-1 Antibody Pembrolizumab. Hutchins, B., Starling, GC., McCoy, MA., et al.[2021]

In a long-term study of 123 patients with advanced nonsquamous NSCLC, the combination of pembrolizumab with pemetrexed-carboplatin significantly improved the objective response rate (58% vs. 33%) and progression-free survival (24.5 months vs. 9.9 months) compared to chemotherapy alone.

Patients who completed 2 years of pembrolizumab treatment had a remarkable 92% survival rate at the data cutoff, indicating a durable clinical benefit, while the safety profile remained manageable with no new safety concerns identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Overall Survival From KEYNOTE-021 Cohort G: Pemetrexed and Carboplatin With or Without Pembrolizumab as First-Line Therapy for Advanced Nonsquamous NSCLC. Awad, MM., Gadgeel, SM., Borghaei, H., et al.[2021]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating advanced melanoma, showing an overall response rate of 24% in a trial of 89 patients, with 86% of responses lasting at least 6 months.

While there are potential immune-mediated side effects, the benefits of prolonged tumor response durations were deemed to outweigh these risks, marking an improvement over existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. Chuk, MK., Chang, JT., Theoret, MR., et al.[2021]

A 68-year-old patient with stage IV lung adenocarcinoma showed an unexpected positive response to paclitaxel after failing treatment with pembrolizumab, an anti-PD-1 immunotherapy.

The patient experienced a response duration of over fourteen months with paclitaxel, suggesting that combining or sequencing chemotherapy with immunotherapy may enhance treatment effectiveness in certain cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Prolonged response with paclitaxel after immunotherapy by pembrolizumab in lung cancer]. Zapata, E., Mennecier, B., Leduc, C., et al.[2017]

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

Pembrolizumab, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

Pembrolizumab (Keytruda) was approved by the FDA for treating metastatic non-small cell lung cancer (mNSCLC) in patients with tumors expressing PD-L1, showing significant improvements in overall survival (OS) and progression-free survival (PFS) in two major clinical trials with thousands of participants.

In the KEYNOTE-024 trial, pembrolizumab demonstrated a 40% reduction in the risk of death compared to chemotherapy, while in the KEYNOTE-010 trial, it also showed a significant survival advantage over chemotherapy in patients who had previously progressed on treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for Treatment of Metastatic Non-Small Cell Lung Cancer: First-Line Therapy and Beyond. Pai-Scherf, L., Blumenthal, GM., Li, H., et al.[2022]

In a phase II study involving 124 patients with metastatic MSI-H/dMMR colorectal cancer, pembrolizumab demonstrated an objective response rate of 33% in both treatment cohorts, indicating its efficacy in this difficult-to-treat population.

The treatment showed a manageable safety profile, with 16% of patients in cohort A and 13% in cohort B experiencing grade 3-4 adverse events, suggesting that pembrolizumab can be safely administered to patients with prior treatment failures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: KEYNOTE-164. Le, DT., Kim, TW., Van Cutsem, E., et al.[2021]

Citations

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This study illustrates a promising treatment strategy for addressing immune evasion in patients with STK11-mutant NSCLC. Significance: Targeting CoREST with ...

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TNG260 in combination with pembrolizumab (Keytruda) has been dosed in the first patient in a phase 1/2 clinical trial of patients with advanced solid tumors.

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Study of TNG260 and an Anti-PD Antibody in STK11 Mutated ...

Participants with STK11-mutant and KRAS-mutant NSCLC (squamous and non squamous) will receive TNG260 at the identified RP2D in combination with pembrolizumab.

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In preclinical models of STK11-deficient non–small cell lung cancer, TNG260 reprograms the tumor epigenome to upregulate immune genes and ...

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TNG260 is a first-in-class, highly selective CoREST complex inhibitor currently being evaluated with pembrolizumab in the dose expansion phase ...

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Study of TNG260 and an Anti-PD Antibody in STK11 ...

The study is evaluating the pharmacokinetics, pharmacodynamics, safety and efficacy of TNG260 in combination with pembrolizumab in patients with an STK11 loss- ...