KO-2806 + Cabozantinib for Solid Cancers

(FIT-001 Trial)

Recruiting at13 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Kura Oncology, Inc.

Must not be taking: Anticancer agents, FTI, HRAS inhibitors

Disqualifiers: CNS metastases, Autoimmune disorders, Infections, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial is testing KO-2806, a new drug that blocks an enzyme helping cancer cells grow, in adults with advanced solid tumors. The goal is to see if it can slow down or stop tumor growth, either alone or with other treatments.

Will I have to stop taking my current medications?

The trial excludes participants who are currently on certain anticancer treatments, so you may need to stop taking those specific medications. However, the protocol does not specify all medications that must be stopped, so it's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug Cabozantinib in treating solid cancers?

Cabozantinib has shown effectiveness in treating various cancers by targeting specific proteins involved in cancer growth, such as MET and VEGFR2. It has been effective in improving survival in patients with renal cell carcinoma and hepatocellular carcinoma, and ongoing studies are exploring its use in other cancers. ^{1 2 3 4 5}

What safety data exists for Cabozantinib in humans?

Cabozantinib has been studied in various clinical trials for different types of cancer, including renal cell carcinoma, Ewing sarcoma, osteosarcoma, and ovarian cancer. These studies primarily focused on its effectiveness, but they also assessed safety, showing that it can be used in humans, although like many cancer treatments, it may have side effects. ^{1 2 3 6 7}

What makes the drug KO-2806 + Cabozantinib unique for treating solid cancers?

The combination of KO-2806 with Cabozantinib is unique because Cabozantinib is a multi-kinase inhibitor that targets several pathways involved in cancer growth, such as MET, VEGF, and AXL, which are not typically targeted together in standard treatments. This combination may offer a novel approach by potentially enhancing the effectiveness of Cabozantinib in solid cancers. ^{1 3 7 8 9}

Research Team

Eligibility Criteria

Adults with advanced solid tumors, including specific types of colorectal, pancreatic, renal cell carcinoma, and non-small cell lung cancer. Participants must be over 18 with acceptable organ function and measurable disease. Some groups require prior treatments or certain genetic features in their tumors.

Inclusion Criteria

I have had at least one treatment for advanced kidney cancer that included immunotherapy.

My liver, kidneys, hormone levels, and blood counts are all within normal ranges.

I am 18 years old or older.

Exclusion Criteria

I am currently on cancer treatment medication.

I have previously been treated with an FTI or HRAS inhibitor.

I haven't had major surgery in the last 28 days or I've fully recovered from it.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive escalating doses of KO-2806 to assess safety and tolerability

28 days per cycle

Multiple visits per cycle

Dose Expansion

Participants receive validated doses of KO-2806 to further assess efficacy and safety

28 days per cycle, up to 24 months

Multiple visits per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

28 days after last dose

Treatment Details

Interventions

• Cabozantinib (Tyrosine kinase inhibitor)
• KO-2806 (Farnesyl transferase inhibitor)

Trial Overview KO-2806 is being tested both alone and combined with Cabozantinib to see how well it works for treating various advanced solid tumors. The trial will gradually increase doses to find the safest and most effective levels.

Participant Groups

Group I: Arm #3: Advanced or metastatic NSCLC, CRC, or PDAC Experimental Treatment 2 Interventions

Patients with KRAS G12C-mutant locally advanced or metastatic NSCLC, CRC, or PDAC who have received at least 1 prior systemic therapy for advanced or metastatic disease

Group II: Arm #2: Advanced or metastatic RCC Experimental Treatment 2 Interventions

Patients who have received at least 1 prior systemic therapy with IO-based treatment for locally advanced or metastatic RCC

Group III: Arm #1: RAS-altered advanced solid tumors Experimental Treatment 1 Intervention

Patients with advanced solid tumors and the following: * HRAS-mutant and/or amplified tumors (any solid tumor type) * HRAS overexpression (only for HNSCC tumors) * KRAS and/or NRAS and/or HRAS-mutant and/or amplified for NSCLC or CRC * KRAS-mutant and/or amplified PDAC

Who Is Running the Clinical Trial?

Kura Oncology, Inc.

Lead Sponsor

Trials

19

Recruited

1,700+

Mirati Therapeutics Inc.

Industry Sponsor

Trials

73

Recruited

8,900+

Dr. Charles M. Baum

Mirati Therapeutics Inc.

Chief Executive Officer since 2023

MD, PhD

Dr. Joseph Leveque

Mirati Therapeutics Inc.

Chief Medical Officer since 2021

MD

Findings from Research

Cabozantinib shows promising anti-tumor activity in patients with metastatic clear cell renal cell carcinoma (RCC), with a partial response observed in 28% of the 25 heavily pretreated participants.

The treatment demonstrated a median progression-free survival of 12.9 months and a median overall survival of 15.0 months, with a safety profile consistent with other similar therapies, indicating its potential as a viable option for advanced RCC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of cabozantinib (XL184) in patients with renal cell cancer. Choueiri, TK., Pal, SK., McDermott, DF., et al.[2021]

In a phase 3 trial involving 658 patients with metastatic renal-cell carcinoma, cabozantinib significantly improved progression-free survival (7.4 months) compared to everolimus (3.8 months), indicating its greater efficacy after VEGFR-targeted therapy.

Cabozantinib also showed a higher objective response rate (21% vs. 5% for everolimus) and a lower risk of progression or death (42% reduction), although both treatments had similar rates of treatment discontinuation due to adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. Choueiri, TK., Escudier, B., Powles, T., et al.[2022]

Cabozantinib demonstrated significant anticancer activity, particularly in ovarian cancer (21.7% objective response rate) and castration-resistant prostate cancer, which showed a median progression-free survival of 5.5 months compared to 1.4 months for placebo.

The trial involved 526 patients, and while cabozantinib showed promising efficacy, nearly half of the patients (48.7%) required dose reductions due to adverse events, with common severe side effects including fatigue, diarrhea, and hypertension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II randomised discontinuation trial of cabozantinib in patients with advanced solid tumours. Schöffski, P., Gordon, M., Smith, DC., et al.[2018]

Cabozantinib (CAB) has shown significant improvements in overall survival and progression-free survival in phase-III studies for patients with advanced renal cell carcinoma and hepatocellular carcinoma, leading to its approval in Japan for these conditions.

CAB may enhance antitumor immunity and, when combined with PD-1 checkpoint inhibitors like nivolumab, has demonstrated increased progression-free survival compared to standard treatments, indicating a potential synergistic effect in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharmacological properties and clinical outcomes of the anti-cancer drug, cabozantinib (CABOMETYX®)]. Osaka, T., Yamaguchi, N., Hara, T.[2022]

In a Phase 1 study involving 12 patients with relapsed osteosarcoma and Ewing sarcoma, the combination of cabozantinib, topotecan, and cyclophosphamide showed acceptable toxicity levels, with manageable dose-limiting toxicities observed.

The treatment resulted in one partial response and stable disease in seven patients, suggesting that this combination therapy may provide potential disease control in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 study of cabozantinib in combination with topotecan-cyclophosphamide for patients with relapsed Ewing sarcoma or osteosarcoma. Campbell, K., Posner, A., Chen, N., et al.[2023]

In a study involving 111 patients with recurrent ovarian cancer, cabozantinib showed a median progression-free survival (PFS) of 5.3 months, which was similar to the 5.5 months achieved with weekly paclitaxel, indicating comparable initial treatment effectiveness.

However, cabozantinib had worse outcomes in overall survival (OS), event-free survival (EFS), and overall response rate (ORR) compared to paclitaxel, along with increased gastrointestinal side effects, leading to the conclusion that cabozantinib is not recommended for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized phase II study of cabozantinib versus weekly paclitaxel in the treatment of persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer: An NRG Oncology/Gynecologic Oncology Group study. Matulonis, UA., Sill, MW., Makker, V., et al.[2020]

The AXL/GAS6 scoring system, developed from a large-scale immunogenomic analysis of renal cell carcinoma (RCC), can effectively predict prognosis in clear cell RCC, indicating its potential as a robust biomarker.

High AXL/GAS6 scores are associated with an immunosuppressive tumor environment and distinct genomic alterations, particularly in the PI3K-mTOR pathway, highlighting the importance of the AXL/GAS6 axis in RCC progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Landscape of prognostic signatures and immunogenomics of the AXL/GAS6 axis in renal cell carcinoma. Hakozaki, K., Tanaka, N., Takamatsu, K., et al.[2022]

In a phase Ib/II study involving 64 patients with progressive non-small cell lung cancer (NSCLC) who had previously received erlotinib, cabozantinib alone showed a modest objective response rate (ORR) of 8.2%, indicating some efficacy as a treatment option.

However, in the phase II portion, the combination of cabozantinib and erlotinib did not yield any responses in patients with acquired resistance to erlotinib, suggesting that cabozantinib did not effectively re-sensitize these patients to erlotinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase Ib/II study of cabozantinib (XL184) with or without erlotinib in patients with non-small cell lung cancer. Wakelee, HA., Gettinger, S., Engelman, J., et al.[2023]

References

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

A phase I study of cabozantinib (XL184) in patients with renal cell cancer. [2021]

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

Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. [2022]

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

Phase II randomised discontinuation trial of cabozantinib in patients with advanced solid tumours. [2018]

4. Japan pubmed.ncbi.nlm.nih.gov

[Pharmacological properties and clinical outcomes of the anti-cancer drug, cabozantinib (CABOMETYX®)]. [2022]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Cabozantinib for metastatic breast carcinoma: results of a phase II placebo-controlled randomized discontinuation study. [2018]

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

Phase 1 study of cabozantinib in combination with topotecan-cyclophosphamide for patients with relapsed Ewing sarcoma or osteosarcoma. [2023]

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

A randomized phase II study of cabozantinib versus weekly paclitaxel in the treatment of persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer: An NRG Oncology/Gynecologic Oncology Group study. [2020]

8. England pubmed.ncbi.nlm.nih.gov

Landscape of prognostic signatures and immunogenomics of the AXL/GAS6 axis in renal cell carcinoma. [2022]

9. Germany pubmed.ncbi.nlm.nih.gov

A phase Ib/II study of cabozantinib (XL184) with or without erlotinib in patients with non-small cell lung cancer. [2023]