IN10018 Monotherapy/Combination for Metastatic Melanoma

Recruiting at 7 trial locations

Overseen By Eddie Xing, Dr.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: InxMed (Shanghai) Co., Ltd.

Must not be taking: FAK inhibitors, MEK inhibitors

Disqualifiers: Diabetes, CNS metastases, autoimmune, 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: 2

120 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, specifically strong and moderate CYP3A inhibitors/inducers and P-gp inhibitors, at least 14 days before starting the study treatment. If you are on these medications, you will need to stop them before participating.

What data supports the effectiveness of the drug combination of Atezolizumab, Tecentriq, Cobimetinib, Cotellic, and IN10018 for metastatic melanoma?

Research shows that combining atezolizumab with cobimetinib and vemurafenib in patients with BRAF-mutated metastatic melanoma resulted in a high response rate, with 71.8% of patients showing a positive response. This suggests that similar combinations, like the one in the trial, may also be effective. ^{1 2 3 4 5}

What safety information is available for IN10018, Atezolizumab, Tecentriq, Cobimetinib, and Cotellic in treating melanoma?

Atezolizumab and cobimetinib have been studied for safety in treating melanoma. Common side effects include anemia (low red blood cell count), headache, high blood pressure, constipation, diarrhea, low thyroid function, weakness, and pain in the limbs. These treatments are generally considered safe and tolerable for patients with advanced melanoma. ^{2 3 4 6 7}

What makes the drug IN10018 combined with Atezolizumab and Cobimetinib unique for treating metastatic melanoma?

This drug combination is unique because it targets both the immune system and specific cancer cell pathways, using Atezolizumab to boost the immune response and Cobimetinib to inhibit cancer cell growth, potentially offering a new option for patients who have progressed on previous treatments. ^{1 2 3 4 8}

What is the purpose of this trial?

This is a phase Ib, open label clinical study to evaluate the safety, tolerability, PK and antitumor activities of IN10018 as monotherapy and in combination with cobimetinib in subjects with metastatic uveal melanoma and NRAS-mutant metastatic melanoma.

Research Team

Eddie Xing, Dr.

Principal Investigator

InxMed Shanghai

Eligibility Criteria

Adults with metastatic uveal melanoma or NRAS-mutant metastatic melanoma, who have either not been treated before, are ineligible for standard care, or whose previous treatments failed. Participants must be willing to provide consent and tissue samples, have a life expectancy of at least 3 months, and meet certain health criteria including organ function. Women must agree to contraception guidelines if applicable.

Inclusion Criteria

I agree to use contraception and not donate sperm during and for 30 days after treatment.

You need to have a recent or stored sample of your tumor tissue available for testing during the screening process.

My cancer did not respond or got worse after immunotherapy.

Exclusion Criteria

Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator

I have cancer that has spread to my brain or spinal cord.

I stopped immunotherapy due to severe side effects.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Monotherapy Treatment

IN10018 is administered as monotherapy to assess safety and tolerability

21 days

Cycle 1

Combination Therapy Part 1

IN10018 is administered in combination with Cobimetinib to assess safety and tolerability

28 days

Cycle 1

Combination Therapy Part 2

IN10018 is administered in combination with Cobimetinib and Atezolizumab to assess safety and tolerability

All treatment period

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

Treatment Details

Interventions

• Atezolizumab
• Cobimetinib
• IN10018

Trial Overview The trial is testing the safety and effectiveness of IN10018 alone and combined with cobimetinib in treating advanced melanoma. It's an early-phase study (phase Ib) where all participants know what treatment they're getting (open label). The goal is to see how well these drugs work against specific types of melanoma.

Participant Groups

Group I: Part 3, Combination Arm Experimental Treatment 3 Interventions

The safety and tolerability of IN10018 in combination with Cobimetinib and Atezolizumab will be assessed.

Group II: Part 2, Combination Arm Experimental Treatment 2 Interventions

The safety and tolerability of IN10018 in combination with Cobimetinib will be assessed. Other dose levels may be explored if necessary. A modified 3+3 design will be used.

Group III: Part 1, Monotherapy Arm Experimental Treatment 1 Intervention

The safety and tolerability of IN10018 monotherapy will be assessed. Other dose levels may be explored if necessary.

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

Approved in United States as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

Approved in European Union as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

Who Is Running the Clinical Trial?

InxMed (Shanghai) Co., Ltd.

Lead Sponsor

Trials

11

Recruited

1,300+

Findings from Research

The combination of atezolizumab (anti-PD-L1) with BRAF and MEK inhibitors showed a high confirmed objective response rate of 71.8% in patients with BRAFV600-mutated metastatic melanoma, indicating strong anti-tumor activity.

This phase Ib study demonstrated that the triple therapy had manageable toxicity and resulted in a median duration of response of 17.4 months, with 39.3% of patients still responding after nearly 30 months, suggesting long-lasting effects of the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients. Sullivan, RJ., Hamid, O., Gonzalez, R., et al.[2022]

In a phase 1b study involving 103 patients with advanced BRAFV600 wild-type melanoma who had progressed on anti-PD-1 therapy, the combination of cobimetinib and atezolizumab showed an objective response rate of 14.6% and a disease control rate of 38.8%.

The treatment was associated with significant adverse events, including diarrhea (72.8%), dermatitis acneiform (55.3%), and nausea (50.5%), highlighting the need for careful monitoring of side effects despite the limited efficacy observed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1b study of cobimetinib plus atezolizumab in patients with advanced BRAFV600 wild-type melanoma progressing on prior anti-programmed death-1 therapy. Sandhu, S., Atkinson, V., Cao, MG., et al.[2023]

In a phase 2 study involving 65 patients with BRAFV600 mutation-positive melanoma and CNS metastases, the combination of atezolizumab with vemurafenib and cobimetinib showed a promising intracranial objective response rate of 42%.

The treatment was associated with significant adverse events, with 68% of patients experiencing grade 3 or worse side effects, highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab, vemurafenib, and cobimetinib in patients with melanoma with CNS metastases (TRICOTEL): a multicentre, open-label, single-arm, phase 2 study. Dummer, R., Queirolo, P., Abajo Guijarro, AM., et al.[2023]

In a phase 2 study involving 65 patients with BRAFV600 mutation-positive melanoma, the combination of atezolizumab, vemurafenib, and cobimetinib showed a significant intracranial objective response rate of 42%, indicating its efficacy in treating CNS metastases.

The treatment was associated with a high incidence of grade 3 or worse adverse events (68% in the BRAFV600 mutation-positive cohort), but no treatment-related deaths were reported, suggesting that while the therapy is effective, it carries a risk of serious side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab, vemurafenib, and cobimetinib in patients with melanoma with CNS metastases (TRICOTEL): a multicentre, open-label, single-arm, phase 2 study. Dummer, R., Queirolo, P., Gerard Duhard, P., et al.[2023]

In a phase 2 study of 185 patients with advanced BRAFV600-mutated melanoma, switching from targeted therapy (vemurafenib + cobimetinib) to atezolizumab after 3 months resulted in significantly shorter progression-free survival (PFS) compared to continuing targeted therapy (13.9 months vs. 5.9 months).

Despite the rapid loss of tumor control with the switch to atezolizumab, there was a numerical overall survival (OS) benefit at 2 years for patients who switched (67% vs. 58% for continued targeted therapy), suggesting potential long-term advantages of the immunotherapy approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early switch from run-in treatment with vemurafenib plus cobimetinib to atezolizumab after 3 months leads to rapid loss of tumour control in patients with advanced BRAFV600-positive melanoma: The ImmunoCobiVem phase 2 randomised trial. Livingstone, E., Gogas, H., Kandolf-Sekulovic, L., et al.[2023]

In a phase 1b study involving 52 patients with advanced melanoma, first-line treatment with atezolizumab showed a confirmed objective response rate of 35%, indicating its effectiveness in this patient population.

Atezolizumab was found to be safe and tolerable, with common side effects including anemia and headache, and a median progression-free survival of 3.7 months, suggesting it can be a viable treatment option for advanced melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line atezolizumab monotherapy in patients with advanced BRAFV600 wild-type melanoma. de Azevedo, SJ., de Melo, AC., Roberts, L., et al.[2022]

Atezolizumab, an anti-PD-L1 therapy, was well tolerated in a study of 45 patients with advanced melanoma, showing that most side effects were mild (grade 1/2) and no treatment-related deaths occurred.

The treatment resulted in a 30% overall response rate and a median overall survival of 23 months, with certain biomarkers like PD-L1 expression and tumor mutational burden linked to better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, Clinical Activity, and Biological Correlates of Response in Patients with Metastatic Melanoma: Results from a Phase I Trial of Atezolizumab. Hamid, O., Molinero, L., Bolen, CR., et al.[2020]

In the coBRIM trial, patients with BRAF (V600) mutation-positive unresectable or metastatic melanoma who received cobimetinib in combination with vemurafenib experienced significantly longer progression-free survival compared to those treated with vemurafenib alone.

The combination treatment also resulted in a higher overall response rate and prolonged overall survival, while maintaining a manageable safety profile, making it a valuable treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cobimetinib Plus Vemurafenib: A Review in BRAF (V600) Mutation-Positive Unresectable or Metastatic Melanoma. Keating, GM.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Phase 1b study of cobimetinib plus atezolizumab in patients with advanced BRAFV600 wild-type melanoma progressing on prior anti-programmed death-1 therapy. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Atezolizumab, vemurafenib, and cobimetinib in patients with melanoma with CNS metastases (TRICOTEL): a multicentre, open-label, single-arm, phase 2 study. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Atezolizumab, vemurafenib, and cobimetinib in patients with melanoma with CNS metastases (TRICOTEL): a multicentre, open-label, single-arm, phase 2 study. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Early switch from run-in treatment with vemurafenib plus cobimetinib to atezolizumab after 3 months leads to rapid loss of tumour control in patients with advanced BRAFV600-positive melanoma: The ImmunoCobiVem phase 2 randomised trial. [2023]

6. England pubmed.ncbi.nlm.nih.gov

First-line atezolizumab monotherapy in patients with advanced BRAFV600 wild-type melanoma. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Safety, Clinical Activity, and Biological Correlates of Response in Patients with Metastatic Melanoma: Results from a Phase I Trial of Atezolizumab. [2020]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Cobimetinib Plus Vemurafenib: A Review in BRAF (V600) Mutation-Positive Unresectable or Metastatic Melanoma. [2019]