Cabozantinib + 13-cis-Retinoic Acid for Solid Tumors

Recruiting at 1 trial location

Overseen By Peter Zage, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Peter Zage

Must not be taking: Anticoagulants, Platelet inhibitors

Disqualifiers: Severe disease, Cardiac disease, Hypertension, Pregnancy, others

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

Compensation: Varies

Number of Visits: 1

Duration: 12 months

18 Participants Needed

Trial Summary

What is the purpose of this trial?

This study is being conducted in order to determine the safety, dose-limiting toxicities, and maximum tolerated dose of cabozantinib in combination with 13-cis-retinoic acid in patients with relapsed or refractory solid tumors including tumors of the central nervous system (CNS)

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

The trial protocol does not specify if you need to stop taking your current medications, but it does mention that you must have recovered from the effects of previous treatments. If you are on steroids, you must be on a stable or decreasing dose for at least one week before starting the study.

What data supports the effectiveness of the drug Cabozantinib + 13-cis-Retinoic Acid for treating solid tumors?

Research shows that 13-cis-retinoic acid has demonstrated anticancer activity in various skin malignancies and has been effective in inhibiting tumor growth in combination with other cancer drugs. Additionally, retinoic acid signaling has been identified as a target for enhancing the effectiveness of cancer treatments, suggesting potential benefits when combined with other therapies like Cabozantinib. ^{1 2 3 4 5}

Is the combination of Cabozantinib and 13-cis-Retinoic Acid safe for humans?

Cabozantinib is generally considered safe for humans and is approved for several types of cancer, including kidney and thyroid cancers. Common side effects include fatigue, diarrhea, and high blood pressure, but these are manageable with proper care. ^{6 7 8 9 10}

What makes the drug combination of Cabozantinib and 13-cis-retinoic acid unique for treating solid tumors?

This drug combination is unique because it combines Cabozantinib, which targets cancer cell growth and blood vessel formation, with 13-cis-retinoic acid, known for its ability to prevent cancer development and slow down tumor growth. This dual approach may offer a novel way to tackle solid tumors by addressing both tumor growth and prevention. ^{4 11 12 13 14}

Research Team

Peter Zage

Principal Investigator

University of California, San Diego

Eligibility Criteria

This trial is for children with solid tumors, including CNS tumors, that have worsened or not responded to standard treatments. They must be mostly recovered from previous therapies and have a performance status score of ≥40. Participants need measurable disease and agree to use contraception. Exclusions include severe diseases, uncontrolled blood pressure, recent major surgery or bleeding events, certain anticoagulation therapies, prior cabozantinib treatment, inability to swallow tablets, allogeneic stem cell transplant recipients or TBI patients.

Inclusion Criteria

Patients must have documentation of either measurable or evaluable disease within 4 weeks of onset of study therapy

My cancer was confirmed by a lab test and has gotten worse or returned after standard treatment.

I agree to use birth control during the study.

Exclusion Criteria

I am not pregnant or breastfeeding.

I have a heart condition.

I cannot swallow whole pills.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive cabozantinib daily and 13-cis-retinoic acid twice daily for two weeks in a 4-week cycle

12 months

Weekly evaluations during the first cycle, monthly thereafter

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 months

Evaluations every three months

Treatment Details

Interventions

• 13-cis-retinoic acid
• Cabozantinib

Trial Overview The study tests the safety and appropriate dosing of cabozantinib combined with 13-cis-retinoic acid in pediatric patients whose solid tumors are resistant to standard care. It aims to find the highest dose that can be given without causing serious side effects (maximum tolerated dose) by gradually increasing doses among participants.

Participant Groups

Group I: Cabozantinib and 13-cis-retinoic acid Experimental Treatment 2 Interventions

Cabozantinib will be given orally once every day with cycles repeated every 4 weeks (28 days, +/- 3 days), with no rest periods between cycles, combined with 13-cis-retinoic acid at 80mg/m2/dose twice daily for two consecutive weeks (14 days) out of every four weeks (28 days, +/- 3 days).

13-cis-retinoic acid is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Isotretinoin for:

• Severe cystic acne
• Harlequin-type ichthyosis
• Lamellar ichthyosis

Approved in United States as Accutane for:

• Severe cystic acne
• Harlequin-type ichthyosis
• Lamellar ichthyosis

Approved in Canada as Isotretinoin for:

• Severe cystic acne
• Harlequin-type ichthyosis
• Lamellar ichthyosis

Who Is Running the Clinical Trial?

Peter Zage

Lead Sponsor

Trials

1

Recruited

20+

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

Oral isotretinoin showed significant efficacy in treating advanced squamous cell carcinoma of the skin in a case series of four patients, with response durations ranging from 2 to over 23 months after treatment.

The treatment was generally well-tolerated, causing only reversible moderate side effects, and suggests that retinoids could be a promising option for patients who do not respond to standard therapies, warranting further clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of advanced squamous cell carcinoma of the skin with isotretinoin. Lippman, SM., Meyskens, FL.[2019]

Approximately 23-32% of human ERBB2(+) breast cancers exhibit coamplification of the retinoic acid receptor alpha (RARA), indicating a novel subtype that is particularly sensitive to all-trans retinoic acid (ATRA) and RARα agonists.

Combining ATRA with lapatinib in estrogen-receptor-negative models that coamplify ERBB2 and RARA leads to enhanced growth inhibition and apoptosis, suggesting a targeted therapy approach with low toxicity for this breast cancer subtype.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synergistic antitumor activity of lapatinib and retinoids on a novel subtype of breast cancer with coamplification of ERBB2 and RARA. Paroni, G., Fratelli, M., Gardini, G., et al.[2018]

The study identified that the retinoic acid (RA) signaling pathway plays a crucial role in the effectiveness of histone deacetylase inhibitors (HDACI) in cancer treatment, as certain genes can confer resistance to these drugs.

Combining RA with HDACI not only enhances the activation of RA signaling but also synergistically inhibits tumor growth, suggesting a potential strategy to improve the therapeutic efficacy of HDACI in cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A functional genetic screen identifies retinoic acid signaling as a target of histone deacetylase inhibitors. Epping, MT., Wang, L., Plumb, JA., et al.[2021]

13-cis-retinoic acid has shown significant potential as an anticancer agent in treating various skin conditions, demonstrating strong antipromoter effects in animal models and antiproliferative activity in vitro.

While effective, the use of 13-cis-retinoic acid is limited by its side effects, particularly on the skin and subcutaneous tissues, which restricts the ability to increase dosages safely.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

13-Cis-retinoic acid: pharmacology, toxicology, and clinical applications for the prevention and treatment of human cancer. Meyskens, FL., Goodman, GE., Alberts, DS.[2019]

Synthetic retinoids that selectively target RXR can effectively inhibit growth and induce apoptosis in trans-RA-resistant breast cancer cells, particularly the MDA-MB-231 cell line, which lacks RAR alpha.

The mechanism of action involves RXR-nur77 heterodimers activating the RARbeta promoter, suggesting that low levels of RAR alpha in certain cancer cells can shift the growth inhibition pathway from RAR-mediated to RXR-mediated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibition of trans-retinoic acid-resistant human breast cancer cell growth by retinoid X receptor-selective retinoids. Wu, Q., Dawson, MI., Zheng, Y., et al.[2021]

The combination of cabozantinib and abiraterone was well-tolerated in patients with metastatic castration-resistant prostate cancer (mCRPC), with no dose-limiting toxicities observed at the initial dose levels during the first 4 weeks of treatment.

Preliminary efficacy results showed that the median overall survival was significantly improved at the 40 mg dose of cabozantinib, reaching 39.08 months, compared to 23.29 months at the 20 mg dose, indicating that 40 mg is the recommended phase 2 dose (RP2D) for further studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A dose finding clinical trial of cabozantinib (XL184) administered in combination with abiraterone acetate in metastatic castration-resistant prostate cancer. Choudhury, AD., Gray, KP., Supko, JG., et al.[2023]

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]

Cabozantinib is an oral multitargeted tyrosine kinase inhibitor approved for advanced renal cell carcinoma and progressive metastatic medullary thyroid cancer, showing potential advantages over single-receptor TKIs.

The article reviews clinical trial data and management strategies for common adverse events associated with cabozantinib, highlighting its expanding use in treating various cancers such as prostate, hepatocellular, and lung cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib: A Multitargeted Oral Tyrosine Kinase Inhibitor. Markowitz, JN., Fancher, KM.[2019]

Cabozantinib is well tolerated in patients with acute myeloid leukemia (AML) at a maximum tolerated dose of 40 mg daily, with no dose-limiting toxicities observed at this level.

The drug demonstrated potent and sustained inhibition of FLT3/ITD and F691 tyrosine kinase domain mutations, indicating its potential efficacy in targeting specific pathways involved in AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib is well tolerated in acute myeloid leukemia and effectively inhibits the resistance-conferring FLT3/tyrosine kinase domain/F691 mutation. Fathi, AT., Blonquist, TM., Hernandez, D., et al.[2021]

In a study involving 132 patients with metastatic castration-resistant prostate cancer, the combination of cabozantinib and atezolizumab demonstrated an objective response rate of 23%, indicating promising antitumor activity after prior hormonal therapies.

While the treatment showed efficacy, 55% of patients experienced grade 3-4 treatment-related adverse events, with pulmonary embolism and diarrhea being the most common, suggesting that while the combination is effective, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer: results from an expansion cohort of a multicentre, open-label, phase 1b trial (COSMIC-021). Agarwal, N., McGregor, B., Maughan, BL., et al.[2022]

In a study involving male Sprague-Dawley and Wister/Furth rats, 13-cis-retinoic acid (13-cis-RA) significantly delayed the onset of colon cancer induced by 1,2-dimethylhydrazine (DMH), indicating its potential role in cancer prevention.

However, when tested on established tumors in Brown Norwegian X Wister/Furth F1 rats, 13-cis-RA did not affect tumor growth or metastasis, suggesting it is not effective as a treatment for existing colon cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of 13-cis-retinoic acid on tumor prevention, tumor growth, and metastasis in experimental colon cancer. O'Dwyer, PJ., Ravikumar, TS., McCabe, DP., et al.[2019]

In a trial involving 20 patients at high risk for bladder tumors, treatment with 13-cis-retinoic acid (CRA) showed a high rate of toxicity, with nearly all patients experiencing side effects such as cheilosis and conjunctivitis.

Despite the initial promise of CRA in animal studies, the treatment did not yield positive results in preventing tumor recurrence, leading to the termination of the study after six months due to the lack of efficacy and severe adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

13-cis-retinoic acid in chemoprevention of superficial bladder cancer. The National Bladder Cancer Group. Prout, GR., Barton, BA.[2013]

In a phase I study involving 51 patients with advanced solid tumors, the combination of belinostat and 13-cis-retinoic acid was well-tolerated, with no maximum tolerated dose (MTD) reached even at doses higher than the established MTD for belinostat alone.

The treatment showed promising results, with ten patients experiencing stable disease and partial responses in two patients, indicating potential efficacy of this combination therapy in managing advanced solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of belinostat in combination with 13-cis-retinoic acid in advanced solid tumor malignancies: a California Cancer Consortium NCI/CTEP sponsored trial. Luu, T., Frankel, P., Beumer, JH., et al.[2020]

13-cis-retinoic acid (13-CRA) alone or in combination with tamoxifen (TAM) did not show effectiveness against established human breast tumors in athymic nude mice, indicating limited therapeutic potential for this treatment approach.

While 13-CRA was metabolized consistently across different tissues, its addition to TAM did not enhance tumor growth delay compared to TAM alone, suggesting that 13-CRA does not improve the efficacy of TAM in treating estrogen-receptor-positive breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity, distribution, and metabolism of 13-cis-retinoic acid as a single agent or in combination with tamoxifen in established human MCF-7 xenografts in mice. Conley, BA., Ramsland, TS., Sentz, DL., et al.[2013]

References

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

Treatment of advanced squamous cell carcinoma of the skin with isotretinoin. [2019]

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

Synergistic antitumor activity of lapatinib and retinoids on a novel subtype of breast cancer with coamplification of ERBB2 and RARA. [2018]

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

A functional genetic screen identifies retinoic acid signaling as a target of histone deacetylase inhibitors. [2021]

4. Netherlands pubmed.ncbi.nlm.nih.gov

13-Cis-retinoic acid: pharmacology, toxicology, and clinical applications for the prevention and treatment of human cancer. [2019]

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

Inhibition of trans-retinoic acid-resistant human breast cancer cell growth by retinoid X receptor-selective retinoids. [2021]

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

A dose finding clinical trial of cabozantinib (XL184) administered in combination with abiraterone acetate in metastatic castration-resistant prostate cancer. [2023]

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

New Indication for Cabozantinib. [2023]

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

Cabozantinib: A Multitargeted Oral Tyrosine Kinase Inhibitor. [2019]

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

Cabozantinib is well tolerated in acute myeloid leukemia and effectively inhibits the resistance-conferring FLT3/tyrosine kinase domain/F691 mutation. [2021]

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

Cabozantinib in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer: results from an expansion cohort of a multicentre, open-label, phase 1b trial (COSMIC-021). [2022]

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

Effect of 13-cis-retinoic acid on tumor prevention, tumor growth, and metastasis in experimental colon cancer. [2019]

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

13-cis-retinoic acid in chemoprevention of superficial bladder cancer. The National Bladder Cancer Group. [2013]

13. Germany pubmed.ncbi.nlm.nih.gov

Phase I trial of belinostat in combination with 13-cis-retinoic acid in advanced solid tumor malignancies: a California Cancer Consortium NCI/CTEP sponsored trial. [2020]

14. Germany pubmed.ncbi.nlm.nih.gov

Antitumor activity, distribution, and metabolism of 13-cis-retinoic acid as a single agent or in combination with tamoxifen in established human MCF-7 xenografts in mice. [2013]