A Phase 1/2 interventional study of MEN1611 and Cetuximab in Metastatic Colorectal Cancer, sponsored by Menarini Group. Completed at 28 sites in 7 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2025-05-01.
Sponsored by Menarini Group · Phase 1/2, Interventional, and Treatment
Open-label, dose-confirmation and cohort expansion, multicenter, Phase Ib/II study to assess the anti-tumor activity and safety of MEN1611 in combination with cetuximab for the treatment of participants with phosphatidylinositol 3-kinase, catalytic, alpha polypeptide gene (PIK3CA)-mutated metastatic colorectal cancer.
This Phase Ib/II study investigated the anti-tumor activity and safety of daily oral doses MEN1611 in combination with cetuximab in female and male participants affected by PIK3CA-mutated, neuroblastoma-Kristen-rat sarcoma virus (N-K-RAS) wild-type, and BRAF wild-type metastatic colorectal cancer.
MEN1611 is a potent, selective class I phosphoinositide 3-kinase (PI3K) inhibitor. The maximum tolerated dose of MEN1611 given as single agent was assessed in a Phase I trial in participants with advanced solid tumors.
This Phase Ib/II started with a dose confirmation part (Step 1) to identify the recommended phase 2 dose of MEN1611 given in combination with cetuximab.
The study continued with a cohort expansion (Step 2) to explore the anti-tumor activity of the selected MEN1611 dose level combined with cetuximab with further assessment of safety and tolerability.
Main Inclusion Criteria:
Main Exclusion Criteria:
MEN1611 + Cetuximab
Drug: MEN1611 · Drug: Cetuximab
MEN1611 oral dose administered twice daily for a continuous 28-day cycle.
Cetuximab solution for infusion administered weekly via intravenous infusion.
Phase 1b: Recommended Phase 2 Dose (RP2D) of MEN1611 in Combination With Cetuximab
RP2D was defined as the highest dose level in milligrams (mg) at which no more than 1 participant during the dose confirmation phase (Phase 1b) experienced a dose-limiting toxicity (DLT) during the DLT assessment window (28 days), or the maximum dose judged to be tolerable by the data safety committee.
Time frame: Day 1 through Day 28 of Cycle 1 (28 days/cycle)
Best Overall Response Rate (ORR) of MEN1611 in Combination With Cetuximab
The best ORR was defined as percentage of participants who had a best overall response to therapy of complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) and was defined according to Response Evaluation Criteria in Solid Tumors version 1.1 assessment locally performed using computed tomography scans or magnetic resonance imaging of the chest and abdomen (including pelvis and adrenal glands).
Time frame: Up to 37 Months
Phase 1b: Number of Participants With DLTs for MEN1611
A DLT was defined as any of the following adverse drug reactions (ADRs) related to the combination regimens or to MEN1611 alone and unrelated to the participants' underlying disease or concomitant medication occurring during Cycle 1 over the DLT assessment window of 28 days: any Grade 3 (lasting \>7 days) or Grade 4 increase in aspartate aminotransferase, alanine aminotransferase, or alkaline phosphatase; any Grade ≥3 cardiac disorder or new segmental wall-motion abnormalities; any Grade ≥3 non-hematologic toxicity with the following exceptions: nausea, vomiting, diarrhea, skin rash, hyperglycemia. An ADR was defined as any adverse event suspected by the investigator and/or the sponsor to be related to MEN1611, cetuximab, or both given in combination.
Time frame: Day 1 through Day 28 of Cycle 1 (28 days/cycle)
Plasma Concentration of MEN1611 in Combination With Cetuximab
Blood samples were taken for the analyses of MEN1611 in plasma at designated time points. Results are reported as nanograms/millilitre (ng/mL).
Time frame: Day 22 (1.5 hours postdose) of Cycle 1 (28 days/cycle)
Disease Control Rate (DCR) of MEN1611 in Combination With Cetuximab
DCR was defined as percentage of participants whose disease shrank or remained stable over a certain time period and was calculated based on the sum of the CR, PR, and SD rates according to local assessment.
Time frame: Up to 37 Months
Duration of Response (DOR) of MEN1611 in Combination With Cetuximab
DOR was defined as the time from confirmation of a PR, CR or SD as locally assessed, until the disease had been shown to progress following treatment. Participants with a previous response who did not show a relapse or died without recording a relapse were censored at their last available relapse-free tumor assessment date. Participants with only one tumor assessment after baseline showing a PD were not included in the calculation.
Time frame: Up to 37 months
Progression-free Survival (PFS) of MEN1611 in Combination With Cetuximab
PFS was defined as the number of days between the first study treatment administration to the date of first documented disease progression as per local assessment, relapse or death from any cause. Responding participants and participants who were lost to follow-up were censored at their last tumor assessment date.
Time frame: Up to 37 months
Overall Survival (OS) of MEN1611 in Combination With Cetuximab
OS was defined as the number of days between the first study treatment administration and death from any cause. Participants still alive that had withdrawn from the study were censored using the latest among end of study and follow-up dates. Drop-out participants were considered censored and the last available date in which the participant was known to be alive was considered.
Time frame: Up to 37 months
| Milestone | Phase 1b (Dose Confirmation) | Phase 2 (Cohort Expansion) |
|---|---|---|
| Started | 7 | 22 |
| Received at least 1 dose of study drug | 7 | 22 |
| Completed | 0 | 0 |
| Not completed | 7 | 22 |
| Withdrew: Withdrawal by subject | 0 | 3 |
| Withdrew: Death | 7 | 11 |
| Withdrew: Investigator decision | 0 | 7 |
| Withdrew: Lost to follow-up | 0 | 1 |
RP2D was defined as the highest dose level in milligrams (mg) at which no more than 1 participant during the dose confirmation phase (Phase 1b) experienced a dose-limiting toxicity (DLT) during the DLT assessment window (28 days), or the maximum dose judged to be tolerable by the data safety committee.
| mg | Phase 1b (Dose Confirmation) |
|---|---|
| Phase 1b: Recommended Phase 2 Dose (RP2D) of MEN1611 in Combination With Cetuximab | 48 |
The best ORR was defined as percentage of participants who had a best overall response to therapy of complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) and was defined according to Response Evaluation Criteria in Solid Tumors version 1.1 assessment locally performed using computed tomography scans or magnetic resonance imaging of the chest and abdomen (including pelvis and adrenal glands).
| percentage of participants | Phase 1b (Dose Confirmation) | Phase 2 (Cohort Expansion) |
|---|---|---|
| Complete Response | 0.0 | 7.1 |
| Partial Response | 40.0 | 7.1 |
| Stable Disease | 40.0 | 57.1 |
| Progressive Disease | 20.0 | 28.6 |
A DLT was defined as any of the following adverse drug reactions (ADRs) related to the combination regimens or to MEN1611 alone and unrelated to the participants' underlying disease or concomitant medication occurring during Cycle 1 over the DLT assessment window of 28 days: any Grade 3 (lasting \>7 days) or Grade 4 increase in aspartate aminotransferase, alanine aminotransferase, or alkaline phosphatase; any Grade ≥3 cardiac disorder or new segmental wall-motion abnormalities; any Grade ≥3 non-hematologic toxicity with the following exceptions: nausea, vomiting, diarrhea, skin rash, hyperglycemia. An ADR was defined as any adverse event suspected by the investigator and/or the sponsor to be related to MEN1611, cetuximab, or both given in combination.
| Participants | Phase 1b (Dose Confirmation) |
|---|---|
| Phase 1b: Number of Participants With DLTs for MEN1611 | 0 |
Blood samples were taken for the analyses of MEN1611 in plasma at designated time points. Results are reported as nanograms/millilitre (ng/mL).
| ng/mL | Phase 1b (Dose Confirmation) | Phase 2 (Cohort Expansion) |
|---|---|---|
| Plasma Concentration of MEN1611 in Combination With Cetuximab | 173.37 ± 125.513 | 241.2 ± NA |
DCR was defined as percentage of participants whose disease shrank or remained stable over a certain time period and was calculated based on the sum of the CR, PR, and SD rates according to local assessment.
| percentage of participants | Phase 1b (Dose Confirmation) | Phase 2 (Cohort Expansion) |
|---|---|---|
| Disease Control Rate (DCR) of MEN1611 in Combination With Cetuximab | 80 (28.4 to 99.5) | 71.4 (41.9 to 91.6) |
DOR was defined as the time from confirmation of a PR, CR or SD as locally assessed, until the disease had been shown to progress following treatment. Participants with a previous response who did not show a relapse or died without recording a relapse were censored at their last available relapse-free tumor assessment date. Participants with only one tumor assessment after baseline showing a PD were not included in the calculation.
| days | Phase 1b (Dose Confirmation) | Phase 2 (Cohort Expansion) |
|---|---|---|
| Duration of Response (DOR) of MEN1611 in Combination With Cetuximab | 85 (47 to NA) | 169 (120 to NA) |
PFS was defined as the number of days between the first study treatment administration to the date of first documented disease progression as per local assessment, relapse or death from any cause. Responding participants and participants who were lost to follow-up were censored at their last tumor assessment date.
| days | Phase 1b (Dose Confirmation) | Phase 2 (Cohort Expansion) |
|---|---|---|
| Progression-free Survival (PFS) of MEN1611 in Combination With Cetuximab | 121 (75 to NA) | 162 (57 to 218) |
OS was defined as the number of days between the first study treatment administration and death from any cause. Participants still alive that had withdrawn from the study were censored using the latest among end of study and follow-up dates. Drop-out participants were considered censored and the last available date in which the participant was known to be alive was considered.
| days | Phase 1b (Dose Confirmation) | Phase 2 (Cohort Expansion) |
|---|---|---|
| Overall Survival (OS) of MEN1611 in Combination With Cetuximab | 471 (171 to NA) | 308 (177 to NA) |
Collected over From Day 1 to the end of study (37 months). Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Phase 1b (Dose Confirmation) | 7/7 (100%) | 5/7 (71.4%) | 7/7 (100%) |
| Phase 2 (Cohort Expansion) | 11/22 (50%) | 11/22 (50%) | 22/22 (100%) |
| Event | Phase 1b (Dose Confirmation) | Phase 2 (Cohort Expansion) |
|---|---|---|
| Enterovesical fistulaGastrointestinal disorders | 1/7 | 0/22 |
| Acute kidney injuryRenal and urinary disorders | 1/7 | 0/22 |
| GastroenteritisInfections and infestations | 1/7 | 0/22 |
| HyperglycaemiaMetabolism and nutrition disorders | 1/7 | 1/22 |
| HypomagnesaemiaMetabolism and nutrition disorders | 1/7 | 0/22 |
| Abdominal painGastrointestinal disorders | 0/7 | 2/22 |
| CholangitisHepatobiliary disorders | 0/7 | 2/22 |
| HypotensionVascular disorders | 0/7 | 1/22 |
| Cardio-respiratory arrestCardiac disorders | 0/7 | 1/22 |
| AstheniaGeneral disorders | 0/7 | 1/22 |
| Event | Phase 1b (Dose Confirmation) | Phase 2 (Cohort Expansion) |
|---|---|---|
| RashSkin and subcutaneous tissue disorders | 7/7 | 11/22 |
| DiarrhoeaGastrointestinal disorders | 5/7 | 16/22 |
| HyperglycaemiaMetabolism and nutrition disorders | 3/7 | 13/22 |
| AnaemiaBlood and lymphatic system disorders | 4/7 | 6/22 |
| FatigueGeneral disorders | 3/7 | 1/22 |
| ParonychiaInfections and infestations | 3/7 | 5/22 |
| HypomagnesaemiaMetabolism and nutrition disorders | 3/7 | 8/22 |
| AstheniaGeneral disorders | 0/7 | 9/22 |
| Mucosal inflammationGeneral disorders | 0/7 | 7/22 |
| NauseaGastrointestinal disorders | 1/7 | 7/22 |
Safety Population: all participants who received at least 1 dose of MEN1611.
| Age, Continuous(years) | Phase 1b (Dose Confirmation) | Phase 2 (Cohort Expansion) | Total |
|---|---|---|---|
| Mean | 53.9 ± 12.16 | 58.9 ± 12.38 | 57.7 ± 12.31 |
| Sex: Female, Male(Participants) | Phase 1b (Dose Confirmation) | Phase 2 (Cohort Expansion) | Total |
|---|---|---|---|
| Female | 1 | 11 | 12 |
| Male | 6 | 11 | 17 |
| Ethnicity (NIH/OMB)(Participants) | Phase 1b (Dose Confirmation) | Phase 2 (Cohort Expansion) | Total |
|---|---|---|---|
| Hispanic or Latino | 0 | 0 | 0 |
| Not Hispanic or Latino | 7 | 15 | 22 |
| Unknown or Not Reported | 0 | 7 | 7 |
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Menarini Group