DCC-3116 for Solid Tumors

Recruiting in Palo Alto (17 mi)

+10 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Deciphera Pharmaceuticals LLC

Must not be taking: CYP3A4 inhibitors, P-gp inducers

Disqualifiers: CNS metastases, Heart disease, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial tests a new drug, DCC-3116, alone and with other drugs, in patients with advanced cancers that have specific genetic mutations. The drug works by blocking a pathway that helps cancer cells grow.

Will I have to stop taking my current medications?

You may need to stop taking certain medications before joining the trial. Specifically, you must not have taken strong or moderate inhibitors or inducers of CYP3A4 or P-glycoprotein, including some herbal medications, within 14 days or 5 times the medication's half-life. Additionally, you must stop taking grapefruit products 14 days before starting the study.

What data supports the effectiveness of the drug DCC-3116 for solid tumors?

Research shows that binimetinib, a component of the treatment, is effective in treating melanoma with specific genetic mutations. Additionally, combining BRAF and MEK inhibitors, like binimetinib and trametinib, has shown positive results in treating certain lung cancers, suggesting potential effectiveness in other solid tumors. ^{1 2 3 4 5}

What safety information is available for DCC-3116 and related treatments?

Binimetinib, a related treatment, has been generally well tolerated in clinical trials for various cancers, with common mild side effects like rash and nausea. Some serious side effects, such as retinal issues and pulmonary embolism, have been reported in rare cases. ^{1 5 6 7 8}

What makes the drug combination of DCC-3116, Binimetinib, Sotorasib, and Trametinib unique for treating solid tumors?

This drug combination is unique because it targets multiple pathways involved in tumor growth and survival, potentially offering a more comprehensive approach to treating solid tumors compared to single-agent therapies. Each component, like Sotorasib, which targets a specific mutation in cancer cells, adds a layer of specificity and potential effectiveness. ^{9 10 11 12 13}

Eligibility Criteria

Adults with advanced solid tumors having specific mutations (RAS/MAPK pathway) who've had certain prior treatments can join. They need good organ function, an ECOG score of 0-2, and must not be pregnant or breastfeeding. Contraception is required for both men and women.

Inclusion Criteria

My cancer has a KRAS G12C mutation.

I can provide a new or old sample of my tumor for the study.

I agree to follow the required contraception methods.

Exclusion Criteria

Known human immunodeficiency virus unless the following requirements are met:

I haven't taken any experimental drugs with unknown safety for at least 28 days, or 14 days with approval.

I stopped taking trametinib or binimetinib due to side effects.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

DCC-3116 is administered in escalating doses as monotherapy and in combination with other drugs to determine the maximum tolerated dose

Approximately 18 months

Expansion

DCC-3116 is administered in combination with sotorasib in 28-day cycles to evaluate safety and preliminary efficacy

Approximately 24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Binimetinib (MAPK Pathway Inhibitor)
• DCC-3116 (MAPK Pathway Inhibitor)
• Sotorasib (MAPK Pathway Inhibitor)
• Trametinib (MAPK Pathway Inhibitor)

Trial Overview The trial tests DCC-3116 alone or with trametinib, binimetinib, or sotorasib in two phases: dose escalation to find safe amounts and expansion to see effects on different cancers like colorectal cancer and melanoma.

Participant Groups

Group I: Expansion Cohorts 1, 2, 3 and 4 (Part 2) Experimental Treatment 1 Intervention

Expansion Cohorts 1, 2, 3 and 4 DCC-3116 combinations will not open for enrollment.

Group II: Expansion Cohort 5 (Part 2) Experimental Treatment 2 Interventions

DCC-3116 tablets orally given in combination with sotorasib in 28-day cycles to evaluate safety and preliminary efficacy of participants with NSCLC (with a documented mutation in KRAS G12C).

Group III: Dose Escalation (Part 1, Cohort D Combination) Experimental Treatment 2 Interventions

Upon determination of the RP2D/MTD single agent, DCC-3116 will be dosed in combination with sotorasib.

Group IV: Dose Escalation (Part 1, Cohort C Combination) Experimental Treatment 2 Interventions

Upon determination of the RP2D/MTD single agent, DCC-3116 will be dosed in combination with binimetinib. Escalation Cohort C combination closed on January 8, 2024.

Group V: Dose Escalation (Part 1, Cohort B Combination) Experimental Treatment 2 Interventions

Upon determination of the RP2D/MTD single agent, DCC-3116 will be dosed in combination with trametinib. Escalation Cohort B combination closed on January 8, 2024.

Group VI: Dose Escalation (Part 1, Cohort A Monotherapy) Experimental Treatment 1 Intervention

DCC-3116 tablets in escalating dose cohorts given orally twice daily (BID) in 28-day cycles as monotherapy (single agent). If no DLT in 3 participants or 1 DLT/6 participants is observed, dose escalation may continue to the next planned dose cohort.

Binimetinib is already approved in United States, European Union, Canada, Japan for the following indications:

🇺🇸 Approved in United States as Mektovi for:

• Unresectable or metastatic melanoma with a BRAF V600E or V600K mutation

🇪🇺 Approved in European Union as Mektovi for:

• Unresectable or metastatic melanoma with a BRAF V600 mutation

🇨🇦 Approved in Canada as Mektovi for:

• Unresectable or metastatic melanoma with a BRAF V600E or V600K mutation

🇯🇵 Approved in Japan as Mektovi for:

• Unresectable or metastatic melanoma with a BRAF V600 mutation

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Rutgers Cancer Institute New Brunswick, NJ

NEXT Oncology San Antonio, TX

Washington University Siteman Cancer Center Saint Louis, MO

Siteman Cancer Center Saint Louis, MO

More Trial Locations

Who Is Running the Clinical Trial?

Deciphera Pharmaceuticals LLC Lead Sponsor

Deciphera Pharmaceuticals, LLC Lead Sponsor

References

1. England pubmed.ncbi.nlm.nih.gov

The discovery and development of binimetinib for the treatment of melanoma. [2021] Label="INTRODUCTION">Binimetinib is an uncompetitive, small-molecule inhibitor of selective mitogen-activated protein kinase (MEK1/2) and was recently approved in 2018 in combination with encorafenib for the treatment of metastatic melanomas. Preclinical and clinical trial data on the drug demonstrate its potent efficacy in cancers, especially melanomas with BRAF and NRAS mutations.

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

Biomarker results from a phase II study of MEK1/2 inhibitor binimetinib (MEK162) in patients with advanced NRAS- or BRAF-mutated melanoma. [2020] BRAF and RAS are the most frequently mutated mitogen-activated protein kinase (MAPK) genes in melanoma. Binimetinib is a highly selective MAPK kinase (MEK) 1/2 inhibitor with clinical antitumor activity in NRAS- and BRAF V600-mutant melanoma. We performed a nonrandomized, open-label phase II study, where 183 metastatic melanoma patients received binimetinib 45 mg / 60 mg twice-daily (BRAF arms), or binimetinib 45 mg twice-daily (NRAS arm). Biomarker analyses were prespecified as secondary and exploratory objectives. Here we report the extent of MAPK pathway inhibition by binimetinib, genetic pathway alterations of interest, and potential predictive markers for binimetinib efficacy. Twenty-five fresh pre- and post-dose tumor sample pairs were collected for biomarker analyses, which included assessment of binimetinib on MEK/MAPK signaling by pharmacodynamic analysis of pERK and DUSP6 expression in pre- vs post-dose tumor biopsies; identification of pERK and DUSP6 expression/efficacy correlations; assessment of baseline tumor molecular status; and exploration of potential predictive biomarkers of efficacy of binimetinib. The postbaseline pERK and DUSP6 expression decreased across all arms; no association between reduced pERK or DUSP6 levels with clinical efficacy was observed. Genetic aberrations were similar to previously reported data on clinical melanoma samples. Genetic pathway alterations occurred predominantly within CDKN2A/B, PTEN, and TRRAP (BRAF-mutation) and CDKN2A/B, TP53, and NOTCH2 (NRAS-mutation). Several patients with BRAF mutations had amplification of genes on chromosome 7q; these patients tended to have shorter progression-free survival than other patients with BRAF-mutant melanoma. Further analysis of genetic alterations, including amplifications of growth factor genes, will determine utility as biomarkers for efficacy.

3. Switzerland pubmed.ncbi.nlm.nih.gov

BRAF Inhibitors in Non-Small Cell Lung Cancer. [2022] RAF family proteins are serine-threonine kinases that play a central role in the MAPK pathway which is involved in embryogenesis, cell differentiation, cell proliferation and death. Deregulation of this pathway is found in up to 30% of all human cancers and BRAF mutations can be identified in 1.5-3.5% of NSCLC patients. Following the positive results obtained through the combination of BRAF and MEK inhibitors in BRAF-mutant melanoma, the same combination was prospectively assessed in BRAF-mutant NSCLC. In cohort B of the BRF113928 trial, 57 pretreated NSCLC patients were treated with dabrafenib plus trametinib: an ORR of 68.4%, a disease control rate of 80.7%, a median PFS of 10.2 months and a median OS of 18.2 months were observed. Similar results were reported in the first-line setting (cohort C), with an ORR of 63.9%, a DCR of 75% and a median PFS and OS of 10.2 and 17.3 months, respectively. The combination was well tolerated: the main adverse events were pyrexia (64%), nausea (56%), diarrhoea (56%), fatigue (36%), oedema (36%) and vomiting (33%). These positive results led to the approval of the combination of dabrafenib and trametinib for the treatment of BRAF V600E metastatic NSCLC patients regardless of previous therapy. Ongoing research should better define the role of new generation RAF inhibitors for patients with acquired resistance, the activity of chemo-immunotherapy or the combination of TKIs with chemotherapy or with immunotherapy in patients with BRAF-mutated cancers.

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

Economic Evaluation of Three BRAF + MEK Inhibitors for the Treatment of Advanced Unresectable Melanoma With BRAF Mutation From a US Payer Perspective. [2023] The combinations of BRAF + MEK inhibitors-encorafenib (ENC) + binimetinib (BIN), cobimetinib (COB) + vemurafenib (VEM), and dabrafenib (DAB) + trametinib (TRA)-are recommended for the treatment of BRAF-mutated advanced melanoma.

5. Germany pubmed.ncbi.nlm.nih.gov

A phase I study of binimetinib (MEK162) in Japanese patients with advanced solid tumors. [2022] Binimetinib is a potent, selective MEK1/2 inhibitor with demonstrated efficacy against BRAF- and RAS-mutant tumors. Retinal adverse events associated with MEK inhibitors have been reported in some cases. The aim of this study was to assess single-agent binimetinib, with detailed ophthalmologic monitoring, in Japanese patients with advanced solid tumors.

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

Phase II, Open-Label Study of Encorafenib Plus Binimetinib in Patients With BRAFV600-Mutant Metastatic Non-Small-Cell Lung Cancer. [2023] Label="PURPOSE">The combination of encorafenib (BRAF inhibitor) plus binimetinib (MEK inhibitor) has demonstrated clinical efficacy with an acceptable safety profile in patients with BRAFV600E/K-mutant metastatic melanoma. We evaluated the efficacy and safety of encorafenib plus binimetinib in patients with BRAFV600E-mutant metastatic non-small-cell lung cancer (NSCLC).

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

Serous Retinopathy Associated with Mitogen-Activated Protein Kinase Kinase Inhibition (Binimetinib) for Metastatic Cutaneous and Uveal Melanoma. [2023] To analyze the clinical characteristics of a serous retinopathy associated with mitogen-activated protein kinase kinase (MEK) inhibition with binimetinib treatment for metastatic cutaneous melanoma (CM) and uveal melanoma (UM), and to determine possible pathogenetic mechanisms that may lead to this retinopathy.

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

Phase 1b investigation of the MEK inhibitor binimetinib in patients with advanced or metastatic biliary tract cancer. [2019] Background The MAPK pathway plays a central role in regulation of several cellular processes, and its dysregulation is a hallmark of biliary tract cancer (BTC). Binimetinib (MEK162), a potent, selective oral MEK1/2 inhibitor, was assessed in patients with advanced BTC. Patients and Methods An expansion cohort study in patients who received ≤1 line of therapy for advanced BTC was conducted after determination of the maximum tolerated dose in this Phase 1 trial. Patients received binimetinib 60 mg twice daily. The primary objectives were to characterize the safety profile and pharmacokinetics of binimetinib in advanced BTC. Secondary objectives included assessment of clinical efficacy, changes in weight and lean body mass, and pharmacodynamic effects. Tumor samples were assessed for mutations in relevant genes. Results Twenty-eight patients received binimetinib. Common adverse events (AEs) were mild, with rash (82%) and nausea (54%) being most common. Two patients experienced grade 4 AEs, one generalized edema and the other pulmonary embolism. The pharmacokinetics in this patient population were consistent with those previously reported (Bendell JC et al., Br J Cancer 2017;116:575-583). Twelve patients (43%) experienced stable disease and two had objective responses (1 complete response, 1 partial response) per Response Evaluation Criteria in Solid Tumors and stable metabolic disease by positron emission tomography/computed tomography. Most patients (18/25; 72%) did not have KRAS, BRAF, NRAS, PI3KCA, or PTEN mutations, nor was there correlation between mutation status and response. The average non-fluid weight gain was 1.3% for lean muscle and 4.7% for adipose tissue. Conclusion Binimetinib was well tolerated and showed promising evidence of activity in patients with BTC. Correlative studies suggested the potential for binimetinib to promote muscle gain in patients with BTC.

9. England pubmed.ncbi.nlm.nih.gov

Sunitinib. [2019] Sunitinib is a small-molecule inhibitor of several receptor tyrosine kinases relevant to tumor angiogenesis, including the vascular endothelial growth factor (VEGF) receptor. Potent inhibition of this related family of receptors and consequent antiangiogenic effects have been demonstrated in vitro and in murine models. Human studies have established 50 mg daily dosing given on an intermittent schedule as a tolerable dose. Significant antitumor effects have been observed, most notably in advanced renal cell carcinoma (RCC) and imatinib refractory/intolerant gastrointestinal stromal tumor (GIST). Sunitinib has received regulatory approval in these two indications, and is at present being investigated across a broad array of solid tumors. Despite these initial results, several questions remain to optimize the utility of this agent.

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

Temsirolimus for metastatic desmoplastic small round cell tumor. [2022] Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive neoplasm that mostly occurs in young males. No curative treatment options currently exist for this type of tumor and long-term survival remains poor. In vitro rapamycin induces apoptotic death of JN-DSRCT-1 cells, a possible model for desmoplastic small round cell tumors in which the EWS gene is fused to the WT1 gene. We therefore demonstrate the prolonged activity of temsirolimus, an mTOR-inhibitor, in a patient with DSRCT.

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

Phase 1 dose-escalation trial of tremelimumab plus sunitinib in patients with metastatic renal cell carcinoma. [2020] On the basis of potential additive or synergistic immunostimulatory antitumor effects, in this phase 1 study, the authors evaluated the combination of sunitinib and tremelimumab (CP-675206; an antibody against cytotoxic T-lymphocyte-associated antigen 4 [CTLA4]) in patients with metastatic renal cell carcinoma (mRCC) was evaluated.

12. England pubmed.ncbi.nlm.nih.gov

Imatinib mesylate in desmoplastic small round cell tumors. [2018] To investigate the possible role of imatinib, an inhibitor of the tyrosine kinase activity of PDGF-R, in desmoplastic small round cell tumor (DSRCT).

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

Sintilimab Plus Platinum and Gemcitabine as First-Line Treatment for Advanced or Metastatic Squamous NSCLC: Results From a Randomized, Double-Blind, Phase 3 Trial (ORIENT-12). [2022] The standard chemotherapy for squamous NSCLC (sqNSCLC) includes platinum plus gemcitabine. Sintilimab, an anti-programmed cell death protein 1 antibody, plus platinum and gemcitabine (GP) has revealed encouraging efficacy as first-line therapy for sqNSCLC in a phase 1b study. We conducted a randomized, double-blind, phase 3 study to further compare the efficacy and safety of sintilimab with placebo, both in combination with GP.