Clinical Trials of (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-TET...

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 mutation1. 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 cancer1.
• Advanced disease stage: Patients enrolled have advanced cancer, meaning the disease has spread beyond its original location or cannot be completely removed by surgery1.
• Previous treatment status: Some trial arms specifically include patients who have been previously treated with systemic therapy, meaning they have already received other cancer treatments1.

Enrollment Numbers

The research program plans to enroll different numbers of patients depending on the specific study design1. The monotherapy study in previously treated patients aims to enroll approximately 100 participants1. The combination therapy studies plan to enroll up to 216 patients1. These enrollment numbers are carefully calculated to provide enough data to evaluate the treatment's effectiveness while ensuring patient safety1.

Phase 2 Clinical Trials

All studies are conducted as Phase 2 trials, which serve a specific purpose in the drug development process1. In Phase 2, researchers focus on:

• Efficacy evaluation: Determining whether the treatment actually works in patients with the target condition1
• Safety monitoring: Continuing to assess side effects and how well patients tolerate the treatment1
• Dose optimization: Finding the best dose and schedule for future larger studies1
• Response measurement: Carefully tracking how tumors respond to treatment using standardized criteria1

Study Status

The trials have received authorization to proceed, which means regulatory authorities have reviewed the study plans and approved them to begin enrolling patients1. This authorization indicates that the preliminary safety data and scientific rationale support moving forward with testing in patients1.

Study Population

This monotherapy trial specifically enrolls patients with RAS G12D-mutant NSCLC who have been previously treated with systemic therapy1. These are patients whose cancer has progressed despite receiving other treatments, representing an important population with limited treatment options1. The study plans to enroll approximately 100 participants1.

Primary Objective

The main goal of this monotherapy study is to evaluate the objective response rate (ORR) of zoldonrasib in this patient population1. The ORR measures the percentage of patients whose tumors shrink or disappear after treatment1. This provides important information about whether the drug is effective at controlling cancer growth1.

Response Assessment

Tumor responses are measured using RECIST v1.1 criteria, which stands for Response Evaluation Criteria in Solid Tumors version 1.11. This is a standardized system that doctors and researchers use worldwide to consistently measure whether cancer is responding to treatment1. Using these standardized criteria allows for accurate comparison of results across different studies and treatment approaches1.

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 effectively1.
• Zoldonrasib with pembrolizumab: Pembrolizumab is an immunotherapy drug that helps the immune system fight cancer1. Combining it with zoldonrasib may provide benefits beyond what either drug achieves alone1.
• Zoldonrasib with pembrolizumab and chemotherapy: Some patients receive a three-drug combination that includes traditional chemotherapy along with the targeted and immunotherapy agents1.
• Triple combination with daraxonrasib: The most intensive regimen includes zoldonrasib, daraxonrasib, pembrolizumab, and potentially chemotherapy1.

Study Objectives for Combination Therapy

The combination therapy studies have multiple important objectives. First, researchers evaluate the safety and tolerability of combining these drugs1. When multiple treatments are given together, it is essential to ensure that side effects remain manageable and do not become too severe for patients1.

Second, the studies aim to determine the Recommended Phase 2 Dose Schedule (RP2DS) for the combinations1. This involves finding the optimal dose and timing of each drug when given together to maximize effectiveness while maintaining acceptable tolerability1.

Patient Population

The combination therapy studies enroll patients with advanced RAS G12D-mutated solid tumors, with specific focus on NSCLC1. Up to 216 patients may participate in these combination studies1. The larger enrollment compared to the monotherapy study reflects the need to evaluate multiple different treatment combinations and gather sufficient data on each approach1.

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 criteria1. This measures how many patients experience tumor shrinkage or disappearance1.
• Safety and Tolerability: For combination studies, evaluating how well patients tolerate the treatment combinations is a primary objective1. This includes monitoring side effects, adverse events, and whether patients can continue treatment1.
• Recommended Dose Determination: Identifying the RP2DS for combination regimens is another key primary objective1. This information guides future clinical development and eventual clinical use if the drugs are approved1.

Assessment Methods

Researchers use standardized methods to evaluate treatment outcomes. RECIST v1.1 criteria provide a consistent framework for measuring tumor responses1. Under these criteria, doctors measure tumors using imaging scans (such as CT or MRI) at regular intervals throughout the study1.

Safety is monitored continuously throughout the trials through regular physical examinations, laboratory tests, and patient reporting of symptoms1. This comprehensive monitoring helps identify any concerning side effects early so they can be managed appropriately1.

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 division1. When functioning properly, RAS proteins act like molecular switches that turn cell growth signals on and off as needed1.

However, mutations in RAS genes can cause these proteins to become stuck in the "on" position1. This leads to uncontrolled cell growth, which is a hallmark of cancer1. RAS mutations are found in many different types of cancer, making them important targets for drug development1.

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 growth1.

The G12D mutation is one of several possible mutations that can occur at position 12 of the RAS protein1. 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 together1.

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 medicine1. Rather than treating all lung cancers the same way, this approach targets treatment to patients whose tumors have specific genetic characteristics1.

For patients to be considered for these trials, their tumors must be tested to confirm the presence of the RAS G12D mutation1. This testing is typically performed on a biopsy sample of the tumor using molecular diagnostic techniques1. Only patients whose tumors test positive for this specific mutation are eligible to participate1.

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 growth1. Additionally, targeted therapies may have different side effect profiles compared to traditional chemotherapy, potentially offering better tolerability for some patients1.