In short
This article reviews clinical trials investigating (12M)-(1S,2S)-N-((63S,4S,Z)-11-ETHYL-12-(2-((S)-1-METHOXYETHYL)-5-(4-METHYLPIPERAZIN-1-YL)PYRIDIN-3-YL)-10,10-DIMETHYL-5,7-DIOXO-61,62,63,64,65,66-HEXAHYDRO-11H-8-OXA-2(4,2)-THIAZOLA-1(5,3)-INDOLA-6(1,3)-PYRIDAZINACYCLOUNDECAPHANE-4-YL)-2-METHYLCYCLOPROPANE-1-CARBOXAMIDE, also known as daraxonrasib or RMC-6236. Trials are evaluating this treatment in patients with RAS-mutated cancers, particularly non-small cell lung cancer and pancreatic cancer.
Key points
- Clinical trials are investigating (12M)-(1S,2S)-N-((63S,4S,Z)-11-ETHYL-12-(2-((S)-1-METHOXYETHYL)-5-(4-METHYLPIPERAZIN-1-YL)PYRIDIN-3-YL)-10,10-DIMETHYL-5,7-DIOXO-61,62,63,64,65,66-HEXAHYDRO-11H-8-OXA-2(4,2)-THIAZOLA-1(5,3)-INDOLA-6(1,3)-PYRIDAZINACYCLOUNDECAPHANE-4-YL)-2-METHYLCYCLOPROPANE-1-CARBOXAMIDE (also known as daraxonrasib or RMC-6236) for patients with RAS-mutated cancers. Studies focus primarily on non-small cell lung cancer and metastatic pancreatic ductal adenocarcinoma with specific RAS mutations including G12D, G12C, and other G12 variants. Trials range from Phase 1 to Phase 3, with early-phase studies evaluating safety and determining optimal doses, while advanced-phase trials compare the treatment against standard therapies. Most trials combine this substance with other treatments such as pembrolizumab, chemotherapy, or another investigational drug called zoldonrasib. The largest trials are enrolling between 216 and 460 patients, measuring outcomes like progression-free survival and overall survival.
Overview of Clinical Research
Clinical trials are currently investigating (12M)-(1S,2S)-N-((63S,4S,Z)-11-ETHYL-12-(2-((S)-1-METHOXYETHYL)-5-(4-METHYLPIPERAZIN-1-YL)PYRIDIN-3-YL)-10,10-DIMETHYL-5,7-DIOXO-61,62,63,64,65,66-HEXAHYDRO-11H-8-OXA-2(4,2)-THIAZOLA-1(5,3)-INDOLA-6(1,3)-PYRIDAZINACYCLOUNDECAPHANE-4-YL)-2-METHYLCYCLOPROPANE-1-CARBOXAMIDE, also known as daraxonrasib or RMC-6236, as a potential treatment for cancers with specific genetic mutations. This investigational substance is being evaluated across multiple phases of clinical research, from early safety studies to large comparative trials against standard treatments.
The research program includes five major clinical trials with a total planned enrollment of over 1,700 patients. These trials are designed to evaluate the substance both as a single agent and in combination with other anticancer therapies. All trials have been authorized and are focusing on patients whose tumors carry mutations in the RAS gene, which is one of the most commonly mutated genes in human cancers.
Understanding the Investigational Substance
The substance (12M)-(1S,2S)-N-((63S,4S,Z)-11-ETHYL-12-(2-((S)-1-METHOXYETHYL)-5-(4-METHYLPIPERAZIN-1-YL)PYRIDIN-3-YL)-10,10-DIMETHYL-5,7-DIOXO-61,62,63,64,65,66-HEXAHYDRO-11H-8-OXA-2(4,2)-THIAZOLA-1(5,3)-INDOLA-6(1,3)-PYRIDAZINACYCLOUNDECAPHANE-4-YL)-2-METHYLCYCLOPROPANE-1-CARBOXAMIDE is referred to by its development code RMC-6236 and the generic name daraxonrasib in clinical trial documentation. This investigational drug is being studied specifically for cancers that have mutations in the RAS gene family.
RAS mutations are genetic changes that cause cells to grow and divide uncontrollably. These mutations are found in approximately 30% of all human cancers and have historically been very difficult to target with medications. The specific mutations being studied in these trials include G12D, G12C, and other G12 variants, which refer to changes at position 12 of the RAS protein.
Target Patient Populations and Cancer Types
The clinical trials investigating (12M)-(1S,2S)-N-((63S,4S,Z)-11-ETHYL-12-(2-((S)-1-METHOXYETHYL)-5-(4-METHYLPIPERAZIN-1-YL)PYRIDIN-3-YL)-10,10-DIMETHYL-5,7-DIOXO-61,62,63,64,65,66-HEXAHYDRO-11H-8-OXA-2(4,2)-THIAZOLA-1(5,3)-INDOLA-6(1,3)-PYRIDAZINACYCLOUNDECAPHANE-4-YL)-2-METHYLCYCLOPROPANE-1-CARBOXAMIDE are focused on two primary cancer types:
- Non-small cell lung cancer (NSCLC): The majority of trials are enrolling patients with advanced NSCLC that carries RAS mutations. This includes patients with G12D mutations, G12C mutations, and other RAS mutations.
- Metastatic pancreatic ductal adenocarcinoma (PDAC): One large Phase 3 trial is specifically studying patients with pancreatic cancer that has spread to other parts of the body.
Most trials require that patients have advanced or metastatic cancer, meaning the disease has spread beyond its original location. Many studies specifically enroll patients who have received previous treatments that did not work or stopped working. The pancreatic cancer trial, for example, focuses on patients with previously treated metastatic disease.
Some trials also include patients with other types of RAS-mutated solid tumors, allowing researchers to evaluate the substance in a broader range of cancers beyond lung and pancreatic cancer.
Phase 1 Clinical Trials
Two Phase 1 trials are evaluating (12M)-(1S,2S)-N-((63S,4S,Z)-11-ETHYL-12-(2-((S)-1-METHOXYETHYL)-5-(4-METHYLPIPERAZIN-1-YL)PYRIDIN-3-YL)-10,10-DIMETHYL-5,7-DIOXO-61,62,63,64,65,66-HEXAHYDRO-11H-8-OXA-2(4,2)-THIAZOLA-1(5,3)-INDOLA-6(1,3)-PYRIDAZINACYCLOUNDECAPHANE-4-YL)-2-METHYLCYCLOPROPANE-1-CARBOXAMIDE in combination with other treatments. Phase 1 trials are the earliest stage of testing in humans and focus primarily on safety and determining the appropriate dose.
Subprotocol A: RAS G12C-Mutated NSCLC
This trial (NCT06162221, Subprotocol A) is enrolling 267 patients with RAS G12C-mutated solid tumors, with a focus on NSCLC. The primary objectives are to evaluate the safety and tolerability of RMC-6291 (another investigational drug) in combination with pembrolizumab, with or without (12M)-(1S,2S)-N-((63S,4S,Z)-11-ETHYL-12-(2-((S)-1-METHOXYETHYL)-5-(4-METHYLPIPERAZIN-1-YL)PYRIDIN-3-YL)-10,10-DIMETHYL-5,7-DIOXO-61,62,63,64,65,66-HEXAHYDRO-11H-8-OXA-2(4,2)-THIAZOLA-1(5,3)-INDOLA-6(1,3)-PYRIDAZINACYCLOUNDECAPHANE-4-YL)-2-METHYLCYCLOPROPANE-1-CARBOXAMIDE, and with or without chemotherapy.
A key goal of this study is to define the recommended Phase 2 dose schedule (RP2DS) for RMC-6291 in these combinations specifically for patients with RAS G12C-mutated NSCLC. The RP2DS is the dose and schedule that will be used in later-stage trials based on the balance of effectiveness and side effects observed in Phase 1.
Subprotocol B: RAS-Mutated NSCLC
The second Phase 1 trial (NCT06162221, Subprotocol B) is larger, planning to enroll 356 patients with RAS-mutated NSCLC. This study evaluates (12M)-(1S,2S)-N-((63S,4S,Z)-11-ETHYL-12-(2-((S)-1-METHOXYETHYL)-5-(4-METHYLPIPERAZIN-1-YL)PYRIDIN-3-YL)-10,10-DIMETHYL-5,7-DIOXO-61,62,63,64,65,66-HEXAHYDRO-11H-8-OXA-2(4,2)-THIAZOLA-1(5,3)-INDOLA-6(1,3)-PYRIDAZINACYCLOUNDECAPHANE-4-YL)-2-METHYLCYCLOPROPANE-1-CARBOXAMIDE in combination with pembrolizumab, with or without chemotherapy.
The objective is to evaluate the safety and tolerability of these combinations in patients with advanced RAS-mutated NSCLC. Unlike Subprotocol A, which focuses on the specific G12C mutation, this trial includes patients with various RAS mutations, providing broader information about the substance's safety profile.
Phase 2 Clinical Trials
One Phase 2 trial is investigating (12M)-(1S,2S)-N-((63S,4S,Z)-11-ETHYL-12-(2-((S)-1-METHOXYETHYL)-5-(4-METHYLPIPERAZIN-1-YL)PYRIDIN-3-YL)-10,10-DIMETHYL-5,7-DIOXO-61,62,63,64,65,66-HEXAHYDRO-11H-8-OXA-2(4,2)-THIAZOLA-1(5,3)-INDOLA-6(1,3)-PYRIDAZINACYCLOUNDECAPHANE-4-YL)-2-METHYLCYCLOPROPANE-1-CARBOXAMIDE in patients with RAS G12D-mutated NSCLC. Phase 2 trials continue to evaluate safety but place more emphasis on whether the treatment shows signs of working against cancer.
RAS G12D-Mutated NSCLC Study
This trial (NCT06162221) plans to enroll 216 patients with RAS G12D-mutated NSCLC. The study is evaluating zoldonrasib (RMC-9805) with or without (12M)-(1S,2S)-N-((63S,4S,Z)-11-ETHYL-12-(2-((S)-1-METHOXYETHYL)-5-(4-METHYLPIPERAZIN-1-YL)PYRIDIN-3-YL)-10,10-DIMETHYL-5,7-DIOXO-61,62,63,64,65,66-HEXAHYDRO-11H-8-OXA-2(4,2)-THIAZOLA-1(5,3)-INDOLA-6(1,3)-PYRIDAZINACYCLOUNDECAPHANE-4-YL)-2-METHYLCYCLOPROPANE-1-CARBOXAMIDE in combination with pembrolizumab, with or without chemotherapy.
The primary objectives are to evaluate the safety and tolerability of these combinations and to determine the RP2DS for RMC-9805 with or without (12M)-(1S,2S)-N-((63S,4S,Z)-11-ETHYL-12-(2-((S)-1-METHOXYETHYL)-5-(4-METHYLPIPERAZIN-1-YL)PYRIDIN-3-YL)-10,10-DIMETHYL-5,7-DIOXO-61,62,63,64,65,66-HEXAHYDRO-11H-8-OXA-2(4,2)-THIAZOLA-1(5,3)-INDOLA-6(1,3)-PYRIDAZINACYCLOUNDECAPHANE-4-YL)-2-METHYLCYCLOPROPANE-1-CARBOXAMIDE in combination with pembrolizumab in this specific patient population. This trial is particularly important because it focuses on the G12D mutation, which is one of the most common RAS mutations in lung cancer.
Phase 3 Clinical Trials
Two large Phase 3 trials are comparing (12M)-(1S,2S)-N-((63S,4S,Z)-11-ETHYL-12-(2-((S)-1-METHOXYETHYL)-5-(4-METHYLPIPERAZIN-1-YL)PYRIDIN-3-YL)-10,10-DIMETHYL-5,7-DIOXO-61,62,63,64,65,66-HEXAHYDRO-11H-8-OXA-2(4,2)-THIAZOLA-1(5,3)-INDOLA-6(1,3)-PYRIDAZINACYCLOUNDECAPHANE-4-YL)-2-METHYLCYCLOPROPANE-1-CARBOXAMIDE against standard treatments. Phase 3 trials are the final stage before a drug can be approved for use and are designed to definitively show whether the new treatment is better than existing options.
Metastatic Pancreatic Cancer Trial
The largest trial (2024-516063-89-00) is enrolling 460 patients with previously treated metastatic pancreatic ductal adenocarcinoma. This study compares (12M)-(1S,2S)-N-((63S,4S,Z)-11-ETHYL-12-(2-((S)-1-METHOXYETHYL)-5-(4-METHYLPIPERAZIN-1-YL)PYRIDIN-3-YL)-10,10-DIMETHYL-5,7-DIOXO-61,62,63,64,65,66-HEXAHYDRO-11H-8-OXA-2(4,2)-THIAZOLA-1(5,3)-INDOLA-6(1,3)-PYRIDAZINACYCLOUNDECAPHANE-4-YL)-2-METHYLCYCLOPROPANE-1-CARBOXAMIDE versus the investigator's choice of standard therapy in patients with RAS G12 mutations.
The trial includes multiple standard treatment options as comparators, including:
- Gemcitabine hydrochloride combined with paclitaxel albumin-bound
- FOLFIRINOX regimen (folinic acid, fluorouracil, irinotecan, and oxaliplatin)
- Gemcitabine with various other chemotherapy agents
The primary objective is to compare the effect of treatment with (12M)-(1S,2S)-N-((63S,4S,Z)-11-ETHYL-12-(2-((S)-1-METHOXYETHYL)-5-(4-METHYLPIPERAZIN-1-YL)PYRIDIN-3-YL)-10,10-DIMETHYL-5,7-DIOXO-61,62,63,64,65,66-HEXAHYDRO-11H-8-OXA-2(4,2)-THIAZOLA-1(5,3)-INDOLA-6(1,3)-PYRIDAZINACYCLOUNDECAPHANE-4-YL)-2-METHYLCYCLOPROPANE-1-CARBOXAMIDE versus standard therapy on progression-free survival (PFS) and overall survival (OS) in the RAS G12 population.
RAS-Mutated NSCLC Trial
The second Phase 3 trial (NCT06881784) is enrolling 420 patients with RAS-mutated NSCLC. This study compares the treatment effect of (12M)-(1S,2S)-N-((63S,4S,Z)-11-ETHYL-12-(2-((S)-1-METHOXYETHYL)-5-(4-METHYLPIPERAZIN-1-YL)PYRIDIN-3-YL)-10,10-DIMETHYL-5,7-DIOXO-61,62,63,64,65,66-HEXAHYDRO-11H-8-OXA-2(4,2)-THIAZOLA-1(5,3)-INDOLA-6(1,3)-PYRIDAZINACYCLOUNDECAPHANE-4-YL)-2-METHYLCYCLOPROPANE-1-CARBOXAMIDE (daraxonrasib) versus docetaxel in the RAS (G12X-C) population.
Docetaxel is a chemotherapy drug commonly used as a standard treatment for patients with NSCLC whose cancer has progressed after initial therapy. This trial will provide critical information about whether (12M)-(1S,2S)-N-((63S,4S,Z)-11-ETHYL-12-(2-((S)-1-METHOXYETHYL)-5-(4-METHYLPIPERAZIN-1-YL)PYRIDIN-3-YL)-10,10-DIMETHYL-5,7-DIOXO-61,62,63,64,65,66-HEXAHYDRO-11H-8-OXA-2(4,2)-THIAZOLA-1(5,3)-INDOLA-6(1,3)-PYRIDAZINACYCLOUNDECAPHANE-4-YL)-2-METHYLCYCLOPROPANE-1-CARBOXAMIDE offers advantages over this established treatment option.
Treatment Combinations Being Studied
Most clinical trials are investigating (12M)-(1S,2S)-N-((63S,4S,Z)-11-ETHYL-12-(2-((S)-1-METHOXYETHYL)-5-(4-METHYLPIPERAZIN-1-YL)PYRIDIN-3-YL)-10,10-DIMETHYL-5,7-DIOXO-61,62,63,64,65,66-HEXAHYDRO-11H-8-OXA-2(4,2)-THIAZOLA-1(5,3)-INDOLA-6(1,3)-PYRIDAZINACYCLOUNDECAPHANE-4-YL)-2-METHYLCYCLOPROPANE-1-CARBOXAMIDE in combination with other anticancer treatments rather than as a single agent. This approach is common in modern cancer research, as combining drugs with different mechanisms of action may provide better results than single treatments.
Combination with Immunotherapy
Several trials are combining (12M)-(1S,2S)-N-((63S,4S,Z)-11-ETHYL-12-(2-((S)-1-METHOXYETHYL)-5-(4-METHYLPIPERAZIN-1-YL)PYRIDIN-3-YL)-10,10-DIMETHYL-5,7-DIOXO-61,62,63,64,65,66-HEXAHYDRO-11H-8-OXA-2(4,2)-THIAZOLA-1(5,3)-INDOLA-6(1,3)-PYRIDAZINACYCLOUNDECAPHANE-4-YL)-2-METHYLCYCLOPROPANE-1-CARBOXAMIDE with pembrolizumab, an immunotherapy drug that helps the immune system recognize and attack cancer cells. Pembrolizumab is already approved for treating various types of cancer and works by blocking a protein called PD-1 that prevents immune cells from attacking tumors.
The rationale for this combination is that targeting RAS mutations with (12M)-(1S,2S)-N-((63S,4S,Z)-11-ETHYL-12-(2-((S)-1-METHOXYETHYL)-5-(4-METHYLPIPERAZIN-1-YL)PYRIDIN-3-YL)-10,10-DIMETHYL-5,7-DIOXO-61,62,63,64,65,66-HEXAHYDRO-11H-8-OXA-2(4,2)-THIAZOLA-1(5,3)-INDOLA-6(1,3)-PYRIDAZINACYCLOUNDECAPHANE-4-YL)-2-METHYLCYCLOPROPANE-1-CARBOXAMIDE while simultaneously activating the immune system with pembrolizumab may provide complementary anticancer effects.
Combination with Chemotherapy
Some trials are adding chemotherapy to the combination of (12M)-(1S,2S)-N-((63S,4S,Z)-11-ETHYL-12-(2-((S)-1-METHOXYETHYL)-5-(4-METHYLPIPERAZIN-1-YL)PYRIDIN-3-YL)-10,10-DIMETHYL-5,7-DIOXO-61,62,63,64,65,66-HEXAHYDRO-11H-8-OXA-2(4,2)-THIAZOLA-1(5,3)-INDOLA-6(1,3)-PYRIDAZINACYCLOUNDECAPHANE-4-YL)-2-METHYLCYCLOPROPANE-1-CARBOXAMIDE and pembrolizumab. Chemotherapy uses drugs that kill rapidly dividing cells, including cancer cells. The Phase 1 and Phase 2 trials include treatment arms that evaluate these triple combinations to determine if adding chemotherapy provides additional benefit.
Combination with Other Targeted Therapies
The Phase 2 trial in RAS G12D-mutated NSCLC is investigating the combination of zoldonrasib (RMC-9805) with (12M)-(1S,2S)-N-((63S,4S,Z)-11-ETHYL-12-(2-((S)-1-METHOXYETHYL)-5-(4-METHYLPIPERAZIN-1-YL)PYRIDIN-3-YL)-10,10-DIMETHYL-5,7-DIOXO-61,62,63,64,65,66-HEXAHYDRO-11H-8-OXA-2(4,2)-THIAZOLA-1(5,3)-INDOLA-6(1,3)-PYRIDAZINACYCLOUNDECAPHANE-4-YL)-2-METHYLCYCLOPROPANE-1-CARBOXAMIDE. Both of these investigational drugs target RAS mutations, and combining them may provide more complete blockade of the RAS signaling pathway that drives cancer growth.
Similarly, one Phase 1 trial is evaluating RMC-6291 with or without (12M)-(1S,2S)-N-((63S,4S,Z)-11-ETHYL-12-(2-((S)-1-METHOXYETHYL)-5-(4-METHYLPIPERAZIN-1-YL)PYRIDIN-3-YL)-10,10-DIMETHYL-5,7-DIOXO-61,62,63,64,65,66-HEXAHYDRO-11H-8-OXA-2(4,2)-THIAZOLA-1(5,3)-INDOLA-6(1,3)-PYRIDAZINACYCLOUNDECAPHANE-4-YL)-2-METHYLCYCLOPROPANE-1-CARBOXAMIDE in patients with RAS G12C-mutated cancers. This allows researchers to compare the effects of each drug alone versus the combination.
Study Endpoints and Measurements
Clinical trials use specific measurements called endpoints to determine whether a treatment is working. Different phases of trials focus on different types of endpoints.
Safety and Tolerability Endpoints
All trials evaluating (12M)-(1S,2S)-N-((63S,4S,Z)-11-ETHYL-12-(2-((S)-1-METHOXYETHYL)-5-(4-METHYLPIPERAZIN-1-YL)PYRIDIN-3-YL)-10,10-DIMETHYL-5,7-DIOXO-61,62,63,64,65,66-HEXAHYDRO-11H-8-OXA-2(4,2)-THIAZOLA-1(5,3)-INDOLA-6(1,3)-PYRIDAZINACYCLOUNDECAPHANE-4-YL)-2-METHYLCYCLOPROPANE-1-CARBOXAMIDE include safety as a primary or important secondary objective. Safety endpoints measure what side effects occur, how severe they are, and how often they happen. This information helps researchers understand the risks of the treatment and determine the appropriate dose.
The Phase 1 and Phase 2 trials specifically aim to determine the RP2DS, which is the dose and schedule that balances effectiveness with acceptable side effects. This dose will then be used in larger Phase 3 trials.
Progression-Free Survival
Progression-free survival (PFS) is a primary endpoint in the Phase 3 pancreatic cancer trial. PFS is defined as the time from randomization (when patients are assigned to a treatment group) until disease progression or death from any cause, whichever occurs first.
Disease progression is measured using RECIST v1.1 (Response Evaluation Criteria in Solid Tumors, version 1.1), which is a standardized way to measure tumor size using imaging scans like CT or MRI. The measurements are made by a blinded independent central review (BICR), meaning experts who don't know which treatment patients received evaluate the scans to ensure unbiased assessment.
Overall Survival
Overall survival (OS) is another primary endpoint in the Phase 3 pancreatic cancer trial. OS is defined as the time from randomization until death from any cause. Overall survival is considered the most important measure of treatment benefit because it directly measures how long patients live, regardless of whether their cancer progresses.
Both PFS and OS are critical for understanding whether (12M)-(1S,2S)-N-((63S,4S,Z)-11-ETHYL-12-(2-((S)-1-METHOXYETHYL)-5-(4-METHYLPIPERAZIN-1-YL)PYRIDIN-3-YL)-10,10-DIMETHYL-5,7-DIOXO-61,62,63,64,65,66-HEXAHYDRO-11H-8-OXA-2(4,2)-THIAZOLA-1(5,3)-INDOLA-6(1,3)-PYRIDAZINACYCLOUNDECAPHANE-4-YL)-2-METHYLCYCLOPROPANE-1-CARBOXAMIDE provides meaningful clinical benefit compared to standard treatments in patients with RAS-mutated cancers.