Cabozantinib for Germ Cell Tumors

Recruiting in Palo Alto (17 mi)

Overseen by Jennifer King, MD

Age: Any Age

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Waitlist Available

Sponsor: Nabil Adra

Must not be taking: Kinase inhibitors, Anticoagulants

Disqualifiers: Brain metastases, Active malignancy, Cardiovascular disorders, GI disorders, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Approved in 4 Jurisdictions

Trial Summary

What is the purpose of this trial?

This trial is testing Cabozantinib, a drug that slows down or stops cancer cell growth. It is aimed at patients with germ cell tumors that do not respond to standard treatments. Cabozantinib works by blocking proteins that cancer cells need to grow.

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop taking your current medications. However, you cannot have taken a small molecule kinase inhibitor within 2 weeks before starting the study treatment, and certain anticoagulants are not allowed. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug Cabozantinib for treating germ cell tumors?

Cabozantinib has shown effectiveness in treating various cancers, such as thyroid, ovarian, and prostate cancers, by targeting specific proteins that help tumors grow and spread. This suggests it might also be effective for germ cell tumors, although direct evidence for this specific use is not provided. ^{1 2 3 4 5}

What safety data exists for cabozantinib in humans?

A phase 1 study on cabozantinib in children with solid tumors found it important to determine the maximum tolerated dose and understand its toxicity profile, which helps assess its safety in humans. ^{6 7 8 9 10}

How is the drug Cabozantinib different from other treatments for germ cell tumors?

Cabozantinib is unique because it targets multiple receptor tyrosine kinases, which are proteins involved in the growth of cancer cells, making it potentially effective for tumors that do not respond to standard cisplatin-based chemotherapy. ^{7 11 12 13 14}

Research Team

Jennifer King, MD

Principal Investigator

Indiana University

Eligibility Criteria

This trial is for adults over 18 with incurable, refractory germ cell tumors who have already undergone first-line cisplatin chemotherapy and at least one salvage regimen without success. They should not be candidates for further curative treatments like surgery. Participants must have acceptable organ function and performance status, understand the study protocol, and agree to use contraception if of childbearing potential.

Inclusion Criteria

I am not on blood thinners, or if I am, my dose has been stable.

My cancer is a type of testicular cancer that has come back after treatment.

My kidney function is within the required range and my protein levels in urine are low.

Exclusion Criteria

My intra-abdominal abscess has fully healed.

My high blood pressure is not controlled even with medication.

I don't have another active cancer, except for certain skin cancers, in situ cervical cancer, low-grade prostate cancer, or any cancer I haven't been treated for in over a year.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients are treated with Cabozantinib 60mg orally daily continuously until disease progression, unacceptable toxicity, or trial closure

up to 1 year

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 2 years

Treatment Details

Interventions

• Cabozantinib (Tyrosine Kinase Inhibitor)

Trial Overview The trial is testing Cabozantinib in patients with germ cell tumors that haven't responded to standard therapies. Treatment continues until disease progression or unacceptable side effects occur. The goal is to see how effective this drug is in controlling the disease when other treatments have failed.

Participant Groups

Group I: Cabozantinib Experimental Treatment 1 Intervention

Patients will be treated with Cabozantinib 60mg orally daily continuously until disease progression, unacceptable toxicity, or trial closure.

Cabozantinib is already approved in Canada, Japan for the following indications:

Approved in Canada as Cabometyx for:

• Renal cell carcinoma
• Hepatocellular carcinoma

Approved in Japan as Cabometyx for:

• Renal cell carcinoma

Who Is Running the Clinical Trial?

Nabil Adra

Lead Sponsor

Trials

5

Recruited

190+

Jennifer King

Lead Sponsor

Trials

1

Recruited

50+

Exelixis

Industry Sponsor

Trials

126

Recruited

20,500+

Michael M. Morrissey

Exelixis

Chief Executive Officer since 2010

PhD in Chemistry from Harvard University, BSc in Chemistry from the University of Wisconsin

Vicki L. Goodman

Exelixis

Chief Medical Officer since 2022

MD

Findings from Research

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]

In a phase 1 trial involving 41 children with refractory solid tumors, the maximum tolerated dose (MTD) of cabozantinib was determined to be 40 mg/m2/day, with dose-limiting toxicities including palmar-plantar erythrodysesthesia syndrome and elevated liver enzymes.

The trial showed preliminary efficacy, with four patients achieving a confirmed partial response and seven maintaining stable disease for over six cycles, indicating potential therapeutic activity of cabozantinib in this pediatric population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1 study of cabozantinib in children and adolescents with recurrent or refractory solid tumors, including CNS tumors: Trial ADVL1211, a report from the Children's Oncology Group. Chuk, MK., Widemann, BC., Minard, CG., et al.[2020]

In a real-world study of 206 lung cancer patients, 18% experienced cardiotoxicity, with QTc prolongation being the most common type, highlighting a significant risk associated with tyrosine-kinase inhibitors like osimertinib and crizotinib.

The study found that none of the patients who developed cardiotoxicity would have qualified for certain phase 3 clinical trials, suggesting that these trials may underestimate the true risk of cardiotoxicity in broader patient populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Investigating the efficacy of osimertinib and crizotinib in phase 3 clinical trials on anti-cancer treatment-induced cardiotoxicity: are real-world studies the way forward? Kobat, H., Elkonaissi, I., Foreman, E., et al.[2023]

In a study of 22 patients with cisplatin-resistant germ cell tumors (GCTs), it was found that the majority of these tumors do not express the receptor tyrosine kinases (c-KIT, EGFR, ERB-B2) that are potential targets for new treatments, indicating limited options for therapy.

The research showed no significant differences in the expression of these markers between cisplatin-resistant and chemosensitive GCTs, suggesting that the overexpression of these receptors does not play a role in the resistance of GCTs to chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Absence of c-KIT and members of the epidermal growth factor receptor family in refractory germ cell cancer. Kollmannsberger, C., Mayer, F., Pressler, H., et al.[2018]

The GemPOx protocol, which includes gemcitabine, paclitaxel, and oxaliplatin, resulted in a 69.8% objective response rate in 53 patients with relapsed/refractory germ cell tumors, indicating its efficacy even after multiple lines of prior chemotherapy.

Patients experienced a manageable level of treatment-related side effects, with 15.1% developing febrile neutropenia, while achieving a median overall survival of 15.9 months and a one-year overall survival rate of 72.6%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Gemcitabine, Paclitaxel, and Oxaliplatin Protocol in the Treatment of Relapsed or Refractory Germ Cell Tumours. Aykan, MB., Yildiran, GS., Akcan, E., et al.[2022]

Cisplatin-based combination chemotherapy can cure 70% to 80% of patients with metastatic testicular germ-cell tumors, with the standard treatment being the combination of cisplatin, etoposide, and bleomycin (PEB).

In patients who are refractory to cisplatin, alternative treatments like paclitaxel and gemcitabine have shown limited efficacy, with response rates of 21% and 17% respectively, but gemcitabine was found to have tolerable non-hematological toxicity, making it a potential option in salvage regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of patients with cisplatin-refractory testicular germ-cell cancer. German Testicular Cancer Study Group (GTCSG). Bokemeyer, C., Kollmannsberger, C., Harstrick, A., et al.[2022]

In a study of 23 patients with chemorefractory non-seminomatous germ-cell tumors, KIT was expressed in 48% of cases and EGFR in 65%, indicating these markers are prevalent in difficult-to-treat tumors.

No activating mutations were found in the KIT gene among the patients analyzed, suggesting that while KIT and EGFR are present, they may not be driving factors in the resistance to standard therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expression of KIT and epidermal growth factor receptor in chemotherapy refractory non-seminomatous germ-cell tumors. Madani, A., Kemmer, K., Sweeney, C., et al.[2020]

References

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

New Indication for Cabozantinib. [2023]

2. 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]

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

Antitumor effects of the multi-target tyrosine kinase inhibitor cabozantinib: a comprehensive review of the preclinical evidence. [2022]

4. Germany pubmed.ncbi.nlm.nih.gov

Cabozantinib: a MET, RET, and VEGFR2 tyrosine kinase inhibitor. [2022]

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

A phase 2 randomised discontinuation trial of cabozantinib in patients with ovarian carcinoma. [2019]

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

A phase 1 study of cabozantinib in children and adolescents with recurrent or refractory solid tumors, including CNS tumors: Trial ADVL1211, a report from the Children's Oncology Group. [2020]

7. Germany pubmed.ncbi.nlm.nih.gov

Treatment of refractory germ-cell tumours with single-agent cabazitaxel: a German Testicular Cancer Study Group case series. [2020]

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

ALK-rearranged non-small cell lung cancers: how best to optimize the safety of crizotinib in clinical practice? [2018]

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

Hematologic toxicities of sunitinib in patients with gastrointestinal stromal tumors: a systematic review and meta-analysis. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Investigating the efficacy of osimertinib and crizotinib in phase 3 clinical trials on anti-cancer treatment-induced cardiotoxicity: are real-world studies the way forward? [2023]

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

Absence of c-KIT and members of the epidermal growth factor receptor family in refractory germ cell cancer. [2018]

12. Pakistan pubmed.ncbi.nlm.nih.gov

Efficacy of Gemcitabine, Paclitaxel, and Oxaliplatin Protocol in the Treatment of Relapsed or Refractory Germ Cell Tumours. [2022]

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

Treatment of patients with cisplatin-refractory testicular germ-cell cancer. German Testicular Cancer Study Group (GTCSG). [2022]

14. England pubmed.ncbi.nlm.nih.gov

Expression of KIT and epidermal growth factor receptor in chemotherapy refractory non-seminomatous germ-cell tumors. [2020]