Cabozantinib for Germ Cell Tumors

Overseen By Nabil Adra, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Nabil Adra

Must not be taking: Kinase inhibitors, Anticoagulants

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

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: up to 1 year

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test Cabozantinib, a new treatment option for patients with germ cell tumors unresponsive to standard therapies. The goal is to determine if Cabozantinib can manage the disease when other treatments have failed. It suits individuals who have not benefited from chemotherapy and whose tumors cannot be surgically removed. Participants will take the medication daily until their disease progresses or they experience significant side effects. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that Cabozantinib is likely to be safe for humans?

Research has shown that cabozantinib generally has a safe profile. In one study, patients experienced fewer side effects such as nausea, vomiting, diarrhea, and severe high blood pressure. Another study focused on patients with cancer that had spread to the brain and found that cabozantinib was well-tolerated by them.

These findings suggest that cabozantinib is usually well-tolerated in various situations, but it can still cause side effects. Prospective participants should discuss any concerns with the trial team before joining. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Cabozantinib is unique because it targets multiple pathways that are crucial for tumor growth, specifically MET and VEGFR2, which are often involved in the progression of germ cell tumors. Traditional treatments for germ cell tumors typically include chemotherapy regimens like BEP (bleomycin, etoposide, and cisplatin), which can sometimes lead to significant side effects. Unlike these standard options, cabozantinib is an oral medication, which can offer more convenient dosing for patients. Researchers are excited about this treatment because its multi-targeted approach may provide a new way to combat tumors that are resistant to current therapies.

What evidence suggests that Cabozantinib might be an effective treatment for germ cell tumors?

Research has shown that cabozantinib, the treatment under study in this trial, may help treat stubborn germ cell tumors. One study found it reduced the risk of cancer progression or death by 81% for certain cancer types, giving patients more time before their cancer advanced. Additionally, cabozantinib extended the time patients with other tumors lived without disease progression by four times. These findings suggest cabozantinib could also be effective for germ cell tumors. ^{2 6 7 8 9}

Who Is on the Research Team?

Jennifer King, MD

Principal Investigator

Indiana University

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Cabozantinib

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.

How Is the Trial Designed?

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 European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Cabometyx for:

• Renal cell carcinoma
• Hepatocellular carcinoma

Approved in United States as Cabometyx for:

• Renal cell carcinoma
• Hepatocellular carcinoma

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

JDS Foundation Testis Cancer Clinical Trials Support Fund

Collaborator

Published Research Related to This Trial

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]

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]

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]

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 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]

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]

Cabazitaxel demonstrated limited efficacy in treating multiply relapsed, platinum-refractory germ-cell tumors, with a 12-week progression-free survival rate of 31% and a median overall survival of 23 weeks based on a retrospective analysis of 13 heavily pre-treated patients.

Despite its limited activity, cabazitaxel was well tolerated, with the most common side effect being grade III-IV hematotoxicity in 54% of patients, indicating that it may be a viable option for further investigation in ongoing clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of refractory germ-cell tumours with single-agent cabazitaxel: a German Testicular Cancer Study Group case series. Oing, C., Hentrich, M., Lorch, A., et al.[2020]

Crizotinib is an effective treatment for adults with ALK-rearranged non-small-cell lung cancer, but managing its common side effects is essential for maintaining treatment continuity and achieving optimal survival rates.

While some side effects like visual disturbances and bradycardia are generally mild, serious cardiac and liver-related adverse events require careful monitoring, particularly for QT interval prolongation and liver function, to ensure patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ALK-rearranged non-small cell lung cancers: how best to optimize the safety of crizotinib in clinical practice? Girard, N., Audigier-Valette, C., Cortot, AB., et al.[2018]

Sunitinib is effective for patients with imatinib-resistant gastrointestinal stromal tumors (GIST), but it has a high incidence of hematologic toxicities, affecting 26.2% of patients with anemia, 41.8% with neutropenia, and 36.4% with thrombocytopenia based on a meta-analysis of 2593 patients from 13 studies.

The risk of high-grade neutropenia is particularly concerning, with a relative risk of 10.39 compared to placebo, indicating that careful monitoring and management of these side effects are essential for patients undergoing treatment with sunitinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hematologic toxicities of sunitinib in patients with gastrointestinal stromal tumors: a systematic review and meta-analysis. Jiang, X., Xiong, F., Fu, Q., et al.[2022]

Cabozantinib (Cabometyx) has received approval for the treatment of locally advanced or metastatic differentiated thyroid cancer that has not responded to previous therapies targeting vascular endothelial growth factor receptors.

This approval highlights Cabozantinib's efficacy in addressing a specific type of thyroid cancer that has progressed after other treatments, providing a new option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Indication for Cabozantinib. Aschenbrenner, DS.[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]

Cabozantinib is an effective oral tyrosine kinase inhibitor that targets multiple receptors involved in cancer growth, showing antitumor activity in various cancers and is approved for specific types of advanced cancer.

Preclinical studies suggest that cabozantinib works well in combination with other cancer treatments, including immune checkpoint inhibitors, highlighting its potential for enhanced efficacy when used alongside other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor effects of the multi-target tyrosine kinase inhibitor cabozantinib: a comprehensive review of the preclinical evidence. Santoni, M., Iacovelli, R., Colonna, V., et al.[2022]

Cabozantinib is an effective receptor tyrosine kinase inhibitor that targets multiple pathways involved in tumor growth and metastasis, showing significant activity in various cancer types, including medullary thyroid cancer (MTC) and prostate cancer.

It gained FDA approval for first-line treatment of advanced MTC after demonstrating clinical benefit in trials, and ongoing phase III studies are investigating its efficacy in metastatic prostate cancer, where it has shown promising response rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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

In a phase 2 trial involving 70 ovarian carcinoma patients, cabozantinib showed a 21% objective response rate at week 12, with a median progression-free survival of 5.5 months, indicating its potential effectiveness in treating this type of cancer.

The treatment was associated with manageable side effects, with 70% of patients experiencing tumor regression, although 37% required dose reductions due to adverse events like diarrhea and hypertension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 2 randomised discontinuation trial of cabozantinib in patients with ovarian carcinoma. Vergote, IB., Smith, DC., Berger, R., et al.[2019]

Citations

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A phase II trial evaluating the efficacy of cabozantinib in ... A phase II trial evaluating the efficacy of cabozantinib in the treatment of patients with refractory germ-cell tumors (GCT).

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04876456

A Phase II Trial of Cabozantinib With Patients ... The purpose of the CTO-IUSCCC-0752 study is to investigate the use of Cabozantinib for patients with incurable, refractory germ cell tumors.

3. ir.exelixis.com ir.exelixis.com/news-releases/news-release-details/exelixis-announces-results-subgroup-analysis-cabinet-phase-3

Press Release - Exelixis With a median follow-up for progression-free survival (PFS) of 5.5 months, CABOMETYX reduced the risk of disease progression or death by 81% ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7605393/

Phase I Study of Cabozantinib and Nivolumab Alone or ... CaboNivo and CaboNivoIpi demonstrated manageable toxicities with durable responses and encouraging survival in patients with mUC and other GU tumors. Multiple ...

5. cabometyxhcp.com cabometyxhcp.com/net-treatment/cabinet-data/pnet-efficacy

Previously treated pNET efficacy data CABOMETYX quadrupled median PFS in pNET 1. 78% reduction in risk of progression or death. PFS results in pNET patients across select disease characteristics.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12394869/

Analysis of the Efficacy and Safety of Cabozantinib ... A significant finding in our study was the reduction in adverse events, including nausea, vomiting, diarrhea, and high-grade hypertension, when ...

7. withpower.com withpower.com/trial/phase-3-neoplasms-4-2021-cf2dd

Cabozantinib for Germ Cell Tumors · Info for Participants 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 ...

8. jamanetwork.com jamanetwork.com/journals/jamaoncology/fullarticle/2784989

Activity and Safety of Cabozantinib for Brain Metastases in ... These findings show considerable intracranial activity and an acceptable safety profile of cabozantinib in patients with renal cell carcinoma and brain ...

9. ir.exelixis.com ir.exelixis.com/news-releases/news-release-details/exelixis-announces-phase-1-trial-results-cabozantinib-0

Exelixis Announces Phase 1 Trial Results for Cabozantinib in ... Stable disease (SD) was reported in 56 percent of patients. The ORR for patients with mUC was 38 percent, and 2 of 16 patients achieved a CR, while 2 patients ...