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(2S)-2-CYCLOPENTYL-2-[(5S)-2-[(2R,3R)-3-CYCLOPROPYL-1-METHYLAZIRIDINE-2-CARBONYL]-2,7-DIAZASPIRO[4.4]NONAN-7-YL]-N-[(6S,8S,14S)-21-[5-(4-CYCLOPROPYLPIPERAZIN-1-YL)-2-[(1S)-1-METHOXYETHYL]PYRIDIN-3-YL]-18,18-DIMETHYL-9,15-DIOXO-22-(2,2,2-TRIFLUOROETHYL)-5,16-DIOXA-2,10,22,28-TETRAZAPENTACYCLO[18.5.2.12,6.110,14.023,27]NONACOSA-1(26),20,23(27),24-TETRAEN-8-YL]ACETAMIDE

This article discusses clinical trials investigating (2S)-2-CYCLOPENTYL-2-[(5S)-2-[(2R,3R)-3-CYCLOPROPYL-1-METHYLAZIRIDINE-2-CARBONYL]-2,7-DIAZASPIRO[4.4]NONAN-7-YL]-N-[(6S,8S,14S)-21-[5-(4-CYCLOPROPYLPIPERAZIN-1-YL)-2-[(1S)-1-METHOXYETHYL]PYRIDIN-3-YL]-18,18-DIMETHYL-9,15-DIOXO-22-(2,2,2-TRIFLUOROETHYL)-5,16-DIOXA-2,10,22,28-TETRAZAPENTACYCLO[18.5.2.12,6.110,14.023,27]NONACOSA-1(26),20,23(27),24-TETRAEN-8-YL]ACETAMIDE, also known as zoldonrasib or RMC-9805, for treating non-small cell lung cancer with RAS G12D mutations. These Phase 2 trials evaluate the safety, tolerability, and effectiveness of this treatment alone or combined with other anticancer drugs in patients who have specific genetic mutations in their tumors.

Table of Contents

Overview of Clinical Research

(2S)-2-CYCLOPENTYL-2-[(5S)-2-[(2R,3R)-3-CYCLOPROPYL-1-METHYLAZIRIDINE-2-CARBONYL]-2,7-DIAZASPIRO[4.4]NONAN-7-YL]-N-[(6S,8S,14S)-21-[5-(4-CYCLOPROPYLPIPERAZIN-1-YL)-2-[(1S)-1-METHOXYETHYL]PYRIDIN-3-YL]-18,18-DIMETHYL-9,15-DIOXO-22-(2,2,2-TRIFLUOROETHYL)-5,16-DIOXA-2,10,22,28-TETRAZAPENTACYCLO[18.5.2.12,6.110,14.023,27]NONACOSA-1(26),20,23(27),24-TETRAEN-8-YL]ACETAMIDE, also known by its development code RMC-9805 and generic name zoldonrasib, is currently being evaluated in Phase 2 clinical trials for the treatment of non-small cell lung cancer[1]. These trials specifically focus on patients whose tumors harbor a particular genetic mutation known as RAS G12D[1].

The clinical research program includes multiple study designs examining zoldonrasib both as a single agent (monotherapy) and in combination with other anticancer treatments[1]. These Phase 2 trials represent an important stage in drug development where researchers evaluate how well the treatment works in patients while continuing to monitor its safety profile[1].

The trials are registered under the identifier NCT06162221 and have received authorization to proceed[1]. This research represents a targeted approach to treating lung cancer based on specific genetic characteristics of the tumor rather than treating all lung cancers the same way[1].

Target Population and Patient Selection

The clinical trials investigating (2S)-2-CYCLOPENTYL-2-[(5S)-2-[(2R,3R)-3-CYCLOPROPYL-1-METHYLAZIRIDINE-2-CARBONYL]-2,7-DIAZASPIRO[4.4]NONAN-7-YL]-N-[(6S,8S,14S)-21-[5-(4-CYCLOPROPYLPIPERAZIN-1-YL)-2-[(1S)-1-METHOXYETHYL]PYRIDIN-3-YL]-18,18-DIMETHYL-9,15-DIOXO-22-(2,2,2-TRIFLUOROETHYL)-5,16-DIOXA-2,10,22,28-TETRAZAPENTACYCLO[18.5.2.12,6.110,14.023,27]NONACOSA-1(26),20,23(27),24-TETRAEN-8-YL]ACETAMIDE are designed for very specific patient populations. The primary focus is on individuals with advanced RAS G12D-mutated solid tumors, with particular emphasis on non-small cell lung cancer[1].

Patient Eligibility Criteria

To participate in these trials, patients must meet several important criteria:

  • Confirmed RAS G12D mutation: Patients must have laboratory-confirmed evidence that their tumor carries the specific RAS G12D genetic mutation[1]. This requires genetic testing of tumor tissue to identify the precise mutation.
  • Non-small cell lung cancer diagnosis: The primary cancer type being studied is NSCLC, which is the most common form of lung cancer[1].
  • Advanced disease stage: Patients enrolled have advanced cancer, meaning the disease has spread beyond its original location or cannot be completely removed by surgery[1].
  • Previous treatment status: Some trial arms specifically include patients who have been previously treated with systemic therapy, meaning they have already received other cancer treatments[1].

Enrollment Numbers

The research program plans to enroll different numbers of patients depending on the specific study design[1]. The monotherapy study in previously treated patients aims to enroll approximately 100 participants[1]. The combination therapy studies plan to enroll up to 216 patients[1]. These enrollment numbers are carefully calculated to provide enough data to evaluate the treatment’s effectiveness while ensuring patient safety[1].

Trial Design and Study Structure

The clinical trials investigating (2S)-2-CYCLOPENTYL-2-[(5S)-2-[(2R,3R)-3-CYCLOPENTYL-1-METHYLAZIRIDINE-2-CARBONYL]-2,7-DIAZASPIRO[4.4]NONAN-7-YL]-N-[(6S,8S,14S)-21-[5-(4-CYCLOPROPYLPIPERAZIN-1-YL)-2-[(1S)-1-METHOXYETHYL]PYRIDIN-3-YL]-18,18-DIMETHYL-9,15-DIOXO-22-(2,2,2-TRIFLUOROETHYL)-5,16-DIOXA-2,10,22,28-TETRAZAPENTACYCLO[18.5.2.12,6.110,14.023,27]NONACOSA-1(26),20,23(27),24-TETRAEN-8-YL]ACETAMIDE are structured as interventional studies, meaning researchers actively provide treatment to participants and measure the outcomes[1].

Phase 2 Clinical Trials

All studies are conducted as Phase 2 trials, which serve a specific purpose in the drug development process[1]. In Phase 2, researchers focus on:

  • Efficacy evaluation: Determining whether the treatment actually works in patients with the target condition[1]
  • Safety monitoring: Continuing to assess side effects and how well patients tolerate the treatment[1]
  • Dose optimization: Finding the best dose and schedule for future larger studies[1]
  • Response measurement: Carefully tracking how tumors respond to treatment using standardized criteria[1]

Study Status

The trials have received authorization to proceed, which means regulatory authorities have reviewed the study plans and approved them to begin enrolling patients[1]. This authorization indicates that the preliminary safety data and scientific rationale support moving forward with testing in patients[1].

Monotherapy Study in Previously Treated Patients

One important component of the research program evaluates (2S)-2-CYCLOPENTYL-2-[(5S)-2-[(2R,3R)-3-CYCLOPROPYL-1-METHYLAZIRIDINE-2-CARBONYL]-2,7-DIAZASPIRO[4.4]NONAN-7-YL]-N-[(6S,8S,14S)-21-[5-(4-CYCLOPROPYLPIPERAZIN-1-YL)-2-[(1S)-1-METHOXYETHYL]PYRIDIN-3-YL]-18,18-DIMETHYL-9,15-DIOXO-22-(2,2,2-TRIFLUOROETHYL)-5,16-DIOXA-2,10,22,28-TETRAZAPENTACYCLO[18.5.2.12,6.110,14.023,27]NONACOSA-1(26),20,23(27),24-TETRAEN-8-YL]ACETAMIDE as a monotherapy, meaning patients receive only this single drug without other cancer treatments[1].

Study Population

This monotherapy trial specifically enrolls patients with RAS G12D-mutant NSCLC who have been previously treated with systemic therapy[1]. These are patients whose cancer has progressed despite receiving other treatments, representing an important population with limited treatment options[1]. The study plans to enroll approximately 100 participants[1].

Primary Objective

The main goal of this monotherapy study is to evaluate the objective response rate (ORR) of zoldonrasib in this patient population[1]. The ORR measures the percentage of patients whose tumors shrink or disappear after treatment[1]. This provides important information about whether the drug is effective at controlling cancer growth[1].

Response Assessment

Tumor responses are measured using RECIST v1.1 criteria, which stands for Response Evaluation Criteria in Solid Tumors version 1.1[1]. This is a standardized system that doctors and researchers use worldwide to consistently measure whether cancer is responding to treatment[1]. Using these standardized criteria allows for accurate comparison of results across different studies and treatment approaches[1].

Combination Therapy Studies

In addition to testing (2S)-2-CYCLOPENTYL-2-[(5S)-2-[(2R,3R)-3-CYCLOPROPYL-1-METHYLAZIRIDINE-2-CARBONYL]-2,7-DIAZASPIRO[4.4]NONAN-7-YL]-N-[(6S,8S,14S)-21-[5-(4-CYCLOPROPYLPIPERAZIN-1-YL)-2-[(1S)-1-METHOXYETHYL]PYRIDIN-3-YL]-18,18-DIMETHYL-9,15-DIOXO-22-(2,2,2-TRIFLUOROETHYL)-5,16-DIOXA-2,10,22,28-TETRAZAPENTACYCLO[18.5.2.12,6.110,14.023,27]NONACOSA-1(26),20,23(27),24-TETRAEN-8-YL]ACETAMIDE alone, the research program includes studies evaluating it in combination with other anticancer treatments[1].

Combination Treatment Approaches

The combination therapy studies examine several different treatment regimens:

  • Zoldonrasib with daraxonrasib (RMC-6236): This combination pairs two investigational drugs that may work together to target cancer cells more effectively[1].
  • Zoldonrasib with pembrolizumab: Pembrolizumab is an immunotherapy drug that helps the immune system fight cancer[1]. Combining it with zoldonrasib may provide benefits beyond what either drug achieves alone[1].
  • Zoldonrasib with pembrolizumab and chemotherapy: Some patients receive a three-drug combination that includes traditional chemotherapy along with the targeted and immunotherapy agents[1].
  • Triple combination with daraxonrasib: The most intensive regimen includes zoldonrasib, daraxonrasib, pembrolizumab, and potentially chemotherapy[1].

Study Objectives for Combination Therapy

The combination therapy studies have multiple important objectives. First, researchers evaluate the safety and tolerability of combining these drugs[1]. When multiple treatments are given together, it is essential to ensure that side effects remain manageable and do not become too severe for patients[1].

Second, the studies aim to determine the Recommended Phase 2 Dose Schedule (RP2DS) for the combinations[1]. This involves finding the optimal dose and timing of each drug when given together to maximize effectiveness while maintaining acceptable tolerability[1].

Patient Population

The combination therapy studies enroll patients with advanced RAS G12D-mutated solid tumors, with specific focus on NSCLC[1]. Up to 216 patients may participate in these combination studies[1]. The larger enrollment compared to the monotherapy study reflects the need to evaluate multiple different treatment combinations and gather sufficient data on each approach[1].

Study Objectives and Endpoints

The clinical trials investigating (2S)-2-CYCLOPENTYL-2-[(5S)-2-[(2R,3R)-3-CYCLOPROPYL-1-METHYLAZIRIDINE-2-CARBONYL]-2,7-DIAZASPIRO[4.4]NONAN-7-YL]-N-[(6S,8S,14S)-21-[5-(4-CYCLOPROPYLPIPERAZIN-1-YL)-2-[(1S)-1-METHOXYETHYL]PYRIDIN-3-YL]-18,18-DIMETHYL-9,15-DIOXO-22-(2,2,2-TRIFLUOROETHYL)-5,16-DIOXA-2,10,22,28-TETRAZAPENTACYCLO[18.5.2.12,6.110,14.023,27]NONACOSA-1(26),20,23(27),24-TETRAEN-8-YL]ACETAMIDE have carefully defined objectives and endpoints that guide the research[1].

Primary Endpoints

The primary endpoints are the main measurements that determine whether the trial meets its goals:

  • Objective Response Rate (ORR): For the monotherapy study, the primary endpoint is ORR as assessed by RECIST v1.1 criteria[1]. This measures how many patients experience tumor shrinkage or disappearance[1].
  • Safety and Tolerability: For combination studies, evaluating how well patients tolerate the treatment combinations is a primary objective[1]. This includes monitoring side effects, adverse events, and whether patients can continue treatment[1].
  • Recommended Dose Determination: Identifying the RP2DS for combination regimens is another key primary objective[1]. This information guides future clinical development and eventual clinical use if the drugs are approved[1].

Assessment Methods

Researchers use standardized methods to evaluate treatment outcomes. RECIST v1.1 criteria provide a consistent framework for measuring tumor responses[1]. Under these criteria, doctors measure tumors using imaging scans (such as CT or MRI) at regular intervals throughout the study[1].

Safety is monitored continuously throughout the trials through regular physical examinations, laboratory tests, and patient reporting of symptoms[1]. This comprehensive monitoring helps identify any concerning side effects early so they can be managed appropriately[1].

Understanding RAS G12D Mutations

The clinical trials investigating (2S)-2-CYCLOPENTYL-2-[(5S)-2-[(2R,3R)-3-CYCLOPROPYL-1-METHYLAZIRIDINE-2-CARBONYL]-2,7-DIAZASPIRO[4.4]NONAN-7-YL]-N-[(6S,8S,14S)-21-[5-(4-CYCLOPROPYLPIPERAZIN-1-YL)-2-[(1S)-1-METHOXYETHYL]PYRIDIN-3-YL]-18,18-DIMETHYL-9,15-DIOXO-22-(2,2,2-TRIFLUOROETHYL)-5,16-DIOXA-2,10,22,28-TETRAZAPENTACYCLO[18.5.2.12,6.110,14.023,27]NONACOSA-1(26),20,23(27),24-TETRAEN-8-YL]ACETAMIDE specifically target cancers with RAS G12D mutations[1]. Understanding this genetic change helps explain why this targeted approach is important.

What Are RAS Mutations?

RAS genes are part of the normal genetic makeup of human cells and play important roles in controlling cell growth and division[1]. When functioning properly, RAS proteins act like molecular switches that turn cell growth signals on and off as needed[1].

However, mutations in RAS genes can cause these proteins to become stuck in the “on” position[1]. This leads to uncontrolled cell growth, which is a hallmark of cancer[1]. RAS mutations are found in many different types of cancer, making them important targets for drug development[1].

The G12D Mutation Specifically

The G12D mutation is a specific type of RAS mutation where the amino acid glycine (G) at position 12 in the protein is replaced with aspartic acid (D)[1]. This single change in the protein structure is enough to cause the RAS protein to malfunction and drive cancer growth[1].

The G12D mutation is one of several possible mutations that can occur at position 12 of the RAS protein[1]. Different mutations at this position may behave differently, which is why treatments are being developed to target specific RAS mutations rather than all RAS mutations together[1].

Importance of Mutation-Specific Treatment

The trials investigating (2S)-2-CYCLOPENTYL-2-[(5S)-2-[(2R,3R)-3-CYCLOPROPYL-1-METHYLAZIRIDINE-2-CARBONYL]-2,7-DIAZASPIRO[4.4]NONAN-7-YL]-N-[(6S,8S,14S)-21-[5-(4-CYCLOPROPYLPIPERAZIN-1-YL)-2-[(1S)-1-METHOXYETHYL]PYRIDIN-3-YL]-18,18-DIMETHYL-9,15-DIOXO-22-(2,2,2-TRIFLUOROETHYL)-5,16-DIOXA-2,10,22,28-TETRAZAPENTACYCLO[18.5.2.12,6.110,14.023,27]NONACOSA-1(26),20,23(27),24-TETRAEN-8-YL]ACETAMIDE represent an example of precision medicine or personalized medicine[1]. Rather than treating all lung cancers the same way, this approach targets treatment to patients whose tumors have specific genetic characteristics[1].

For patients to be considered for these trials, their tumors must be tested to confirm the presence of the RAS G12D mutation[1]. This testing is typically performed on a biopsy sample of the tumor using molecular diagnostic techniques[1]. Only patients whose tumors test positive for this specific mutation are eligible to participate[1].

This targeted approach offers potential advantages. By focusing on a specific molecular target, treatments may be more effective in patients whose cancers depend on that target for growth[1]. Additionally, targeted therapies may have different side effect profiles compared to traditional chemotherapy, potentially offering better tolerability for some patients[1].

Trial ID Phase Condition Studied Treatment Approach Status Enrollment
NCT06162221 Phase 2 RAS G12D-mutant NSCLC Zoldonrasib with or without daraxonrasib and pembrolizumab, with or without chemotherapy Authorised 216
NCT06162221 Phase 2 RAS G12D-mutant NSCLC (previously treated) Zoldonrasib monotherapy Authorised 100

FAQ

  • What is (2S)-2-CYCLOPENTYL-2-[(5S)-2-[(2R,3R)-3-CYCLOPROPYL-1-METHYLAZIRIDINE-2-CARBONYL]-2,7-DIAZASPIRO[4.4]NONAN-7-YL]-N-[(6S,8S,14S)-21-[5-(4-CYCLOPROPYLPIPERAZIN-1-YL)-2-[(1S)-1-METHOXYETHYL]PYRIDIN-3-YL]-18,18-DIMETHYL-9,15-DIOXO-22-(2,2,2-TRIFLUOROETHYL)-5,16-DIOXA-2,10,22,28-TETRAZAPENTACYCLO[18.5.2.12,6.110,14.023,27]NONACOSA-1(26),20,23(27),24-TETRAEN-8-YL]ACETAMIDE being tested for? The substance, also known as zoldonrasib (RMC-9805), is being tested in clinical trials for treating non-small cell lung cancer that has a specific genetic mutation called RAS G12D. The trials are evaluating how well it works alone or when combined with other cancer treatments like pembrolizumab and chemotherapy.
  • Who can participate in these clinical trials? These trials are designed for patients with advanced non-small cell lung cancer who have the RAS G12D mutation in their tumors. Some trials specifically include patients who have already received previous systemic therapy for their cancer. The trials are enrolling between 100 to 216 patients depending on the study design.
  • What phase are these clinical trials in? The clinical trials investigating (2S)-2-CYCLOPENTYL-2-[(5S)-2-[(2R,3R)-3-CYCLOPROPYL-1-METHYLAZIRIDINE-2-CARBONYL]-2,7-DIAZASPIRO[4.4]NONAN-7-YL]-N-[(6S,8S,14S)-21-[5-(4-CYCLOPROPYLPIPERAZIN-1-YL)-2-[(1S)-1-METHOXYETHYL]PYRIDIN-3-YL]-18,18-DIMETHYL-9,15-DIOXO-22-(2,2,2-TRIFLUOROETHYL)-5,16-DIOXA-2,10,22,28-TETRAZAPENTACYCLO[18.5.2.12,6.110,14.023,27]NONACOSA-1(26),20,23(27),24-TETRAEN-8-YL]ACETAMIDE are in Phase 2. This phase focuses on determining how effective the treatment is and continues to evaluate its safety in larger groups of patients.
  • What are the main goals of these trials? The trials aim to evaluate the safety and tolerability of the treatment, determine the recommended dose for future studies, and measure the objective response rate (how many patients' tumors shrink or disappear). Researchers are also studying how well the drug works when combined with other cancer therapies like pembrolizumab and chemotherapy.
  • What is RAS G12D mutation and why does it matter? RAS G12D is a specific genetic change (mutation) found in some cancer cells that helps tumors grow. This mutation occurs in the RAS gene, which normally controls cell growth. When mutated, it can cause cells to grow uncontrollably, leading to cancer. The treatment being studied is designed to target this specific mutation.

Ongoing Clinical Trials on (2S)-2-CYCLOPENTYL-2-[(5S)-2-[(2R,3R)-3-CYCLOPROPYL-1-METHYLAZIRIDINE-2-CARBONYL]-2,7-DIAZASPIRO[4.4]NONAN-7-YL]-N-[(6S,8S,14S)-21-[5-(4-CYCLOPROPYLPIPERAZIN-1-YL)-2-[(1S)-1-METHOXYETHYL]PYRIDIN-3-YL]-18,18-DIMETHYL-9,15-DIOXO-22-(2,2,2-TRIFLUOROETHYL)-5,16-DIOXA-2,10,22,28-TETRAZAPENTACYCLO[18.5.2.12,6.110,14.023,27]NONACOSA-1(26),20,23(27),24-TETRAEN-8-YL]ACETAMIDE

Glossary

  • RAS G12D mutation: A specific genetic change in the RAS gene where the amino acid glycine at position 12 is replaced with aspartic acid. This mutation can cause cells to grow abnormally and is found in certain cancers.
  • Non-Small Cell Lung Cancer (NSCLC): The most common type of lung cancer, accounting for about 85% of all lung cancers. It grows and spreads more slowly than small cell lung cancer.
  • Phase 2 clinical trial: A stage of drug testing that evaluates how well a treatment works and continues to assess its safety in a larger group of patients, typically 100-300 people.
  • Objective Response Rate (ORR): The percentage of patients whose tumors shrink or disappear after treatment. This is measured using specific criteria to determine treatment effectiveness.
  • RECIST v1.1: Response Evaluation Criteria in Solid Tumors version 1.1, a standardized method doctors use to measure whether cancer tumors are growing, shrinking, or staying the same during treatment.
  • Pembrolizumab: An immunotherapy drug that helps the body's immune system recognize and fight cancer cells. It is often used in combination with other cancer treatments.
  • Systemic therapy: Treatment that travels through the bloodstream to reach cancer cells throughout the body, including chemotherapy, immunotherapy, and targeted therapy.
  • Advanced cancer: Cancer that has spread from where it started to other parts of the body or cannot be completely removed by surgery. Also called metastatic cancer.
  • Tolerability: How well patients can handle a treatment, including whether side effects are manageable and do not force them to stop taking the medication.
  • RP2DS: Recommended Phase 2 Dose Schedule, the optimal dose and timing of a drug determined to be safe and potentially effective for use in larger clinical trials.
  • Monotherapy: Treatment with a single drug or therapy, rather than a combination of multiple treatments.
  • Solid tumors: Abnormal masses of tissue that do not contain liquid areas or cysts. Most cancers are solid tumors, including lung, breast, and colon cancers.

References