Cabozantinib + 13-cis-Retinoic Acid for Solid Tumors
Recruiting in Palo Alto (17 mi)
+1 other location
Overseen byPeter Zage
Age: < 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Peter Zage
Must not be taking: Anticoagulants, Platelet inhibitors
Disqualifiers: Severe disease, Cardiac disease, Hypertension, Pregnancy, others
No Placebo Group
Breakthrough Therapy
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.
12345Is 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.
678910What 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.
411121314Eligibility 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 β₯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.
+3 more
Exclusion Criteria
I am not pregnant or breastfeeding.
I have a heart condition.
I cannot swallow whole pills.
+13 more
Trial 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
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: Cabozantinib and 13-cis-retinoic acidExperimental Treatment2 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:
πͺπΊ Approved in European Union as Isotretinoin for:
- Severe cystic acne
- Harlequin-type ichthyosis
- Lamellar ichthyosis
πΊπΈ Approved in United States as Accutane for:
- Severe cystic acne
- Harlequin-type ichthyosis
- Lamellar ichthyosis
π¨π¦ Approved in Canada as Isotretinoin for:
- Severe cystic acne
- Harlequin-type ichthyosis
- Lamellar ichthyosis
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Children's Healthcare of AtlantaAtlanta, GA
Rady Children's Hospital - San DiegoSan Diego, CA
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Who Is Running the Clinical Trial?
Peter ZageLead Sponsor
ExelixisIndustry Sponsor
References
Treatment of advanced squamous cell carcinoma of the skin with isotretinoin. [2019]To determine the efficacy of oral isotretinoin in refractory advanced squamous cell carcinoma of the skin.
Synergistic antitumor activity of lapatinib and retinoids on a novel subtype of breast cancer with coamplification of ERBB2 and RARA. [2018]All-trans retinoic acid (ATRA), the only clinically available cyto-differentiating agent, has potential for the therapy/chemoprevention of breast carcinoma. Given the heterogeneous nature of this tumor, a rational use of ATRA and derivatives (retinoids) in the clinic requires the identification of patients that would benefit from retinoid-based protocols. Here, we demonstrate that 23-32% of the human ERBB2(+) breast cancers show coamplification of retinoic acid receptor alpha (RARA), encoding the retinoic acid receptor, RARΞ±. This represents a novel subtype of breast cancer characterized by remarkable sensitivity to ATRA and RARΞ± agonists, regardless of positivity to the estrogen receptor, a known modulator of retinoid sensitivity. In estrogen-receptor-negative cellular models showing coamplification of ERBB2 and RARA, simultaneous targeting of the corresponding gene products with combinations of lapatinib and ATRA causes synergistic growth inhibition, cyto-differentiation and apoptosis. This provides proof-of-principle that coamplification of ERBB2 and RARA can be exploited for the stratified and targeted therapy of a novel subtype of breast cancer patients, with an approach characterized by tumor cell selectivity and low predicted toxicity. The available cellular models were exploited to define the molecular mechanisms underlying the antitumor activity of combinations between lapatinib and ATRA. Global gene expression and functional approaches provide evidence for three components of the antiproliferative/apoptotic responses triggered by lapatinib+ATRA. Induction of the retinoid-dependent RARRES3 protein by ATRA stabilizes the effect of lapatinib inhibiting ERBB2 phosphorylation. Upregulation and activation of the transcription factor FOXO3A integrates ATRA-dependent transcriptional and lapatinib-dependent posttranscriptional signals, controlling the levels of effector proteins like the antiapoptotic factor, BIRC5. Stimulation of the TGFΞ² pathway by ATRA mediates other components of the apoptotic process set in motion by simultaneous targeting of ERBB2 and RARΞ±.
A functional genetic screen identifies retinoic acid signaling as a target of histone deacetylase inhibitors. [2021]Understanding the pathways that are targeted by cancer drugs is instrumental for their rational use in a clinical setting. Inhibitors of histone deacetylases (HDACI) selectively inhibit proliferation of malignant cells and are used for the treatment of cancer, but their cancer selectivity is understood poorly. We conducted a functional genetic screen to address the mechanism(s) of action of HDACI. We report here that ectopic expression of two genes that act on retinoic acid (RA) signaling can cause resistance to growth arrest and apoptosis induced by HDACI of different chemical classes: the retinoic acid receptor alpha (RARalpha) and preferentially expressed antigen of melanoma (PRAME), a repressor of RA signaling. Treatment of cells with HDACI induced RA signaling, which was inhibited by RARalpha or PRAME expression. Conversely, RAR-deficient cells and PRAME-knockdown cells show enhanced sensitivity to HDACI in vitro and in mouse xenograft models. Finally, a combination of RA and HDACI acted synergistically to activate RA signaling and inhibit tumor growth. These experiments identify the RA pathway as a rate-limiting target of HDACI and suggest strategies to enhance the therapeutic efficacy of HDACI.
13-Cis-retinoic acid: pharmacology, toxicology, and clinical applications for the prevention and treatment of human cancer. [2019]Retinoids, particularly 13-cis-retinoic acid, have shown great promise against a number of benign, but serious dermatological conditions. In animal models, 13-cis-retinoic acid functions is a potent antipromoter whether a cancer has been initiated by chemical, physical, or viral agents. Additionally, substantial antiproliferative activity of this compound has been demonstrated in vitro in many culture systems. Clinical activity noted against several types of skin malignancies has led to several investigations to determine the anticancer activity of 13-cis-retinoic acid. Response of a variety of preneoplastic and neoplastic lesions of epithelial histology has been demonstrated. The toxicity of 13-cis-retinoic acid largely reflects its tissue distribution with skin and subcutaneous side-effects limiting dose escalation. The pharmacology and pharmacokinetics of 13-cis-retinoic acid has been explored in a number of patients and a long terminal half-life demonstrated. This review will discuss 13-cis-retinoic acid as a good model for a biological response modifier.
Inhibition of trans-retinoic acid-resistant human breast cancer cell growth by retinoid X receptor-selective retinoids. [2021]All-trans-retinoic acid (trans-RA) and other retinoids exert anticancer effects through two types of retinoid receptors, the RA receptors (RARs) and retinoid X receptors (RXRs). Previous studies demonstrated that the growth-inhibitory effects of trans-RA and related retinoids are impaired in certain estrogen-independent breast cancer cell lines due to their lower levels of RAR alpha and RARbeta. In this study, we evaluated several synthetic retinoids for their ability to induce growth inhibition and apoptosis in both trans-RA-sensitive and trans-RA-resistant breast cancer cell lines. Our results demonstrate that RXR-selective retinoids, particularly in combination with RAR-selective retinoids, could significantly induce RARbeta and inhibit the growth and induce the apoptosis of trans-RA-resistant, RAR alpha-deficient MDA-MB-231 cells but had low activity against trans-RA-sensitive ZR-75-1 cells that express high levels of RAR alpha. Using gel retardation and transient transfection assays, we found that the effects of RXR-selective retinoids on MDA-MB-231 cells were most likely mediated by RXR-nur77 heterodimers that bound to the RA response element in the RARbeta promoter and activated the RARbeta promoter in response to RXR-selective retinoids. In contrast, growth inhibition by RAR-selective retinoids in trans-RA-sensitive, RAR alpha-expressing cells most probably occurred through RXR-RAR alpha heterodimers that also bound to and activated the RARbeta promoter. In MDA-MB-231 clones stably expressing RAR alpha, both RARbeta induction and growth inhibition by RXR-selective retinoids were suppressed, while the effects of RAR-selective retinoids were enhanced. Together, our results demonstrate that activation of RXR can inhibit the growth of trans-RA-resistant MDA-MB-231 breast cancer cells and suggest that low cellular RAR alpha may regulate the signaling switch from RAR-mediated to RXR-mediated growth inhibition in breast cancer cells.
A dose finding clinical trial of cabozantinib (XL184) administered in combination with abiraterone acetate in metastatic castration-resistant prostate cancer. [2023]Cabozantinib can enhance the effect of abiraterone in preclinical prostate cancer models. This study aimed to define the recommended phase 2 dose (RP2D) and preliminary efficacy of abiraterone + cabozantinib in mCRPC.
New Indication for Cabozantinib. [2023]Cabozantinib (Cabometyx) is now approved to treat locally advanced or metastatic differentiated thyroid cancer that has progressed following prior vascular endothelial growth factor receptor-targeted therapy.
Cabozantinib: A Multitargeted Oral Tyrosine Kinase Inhibitor. [2019]Cabozantinib is an oral small-molecule multitargeted tyrosine kinase inhibitor (TKI) that may confer an advantage over other TKIs that target a single receptor. It was approved by the U.S. Food and Drug Administration for the treatment of both advanced renal cell carcinoma and progressive metastatic medullary thyroid cancer, and it is being investigated for a wide array of other malignancies. Rationale for use, clinical trial data, and current recommendations for cabozantinib in renal cell cancer, thyroid cancer, prostate cancer, hepatocellular cancer, and lung cancer are detailed in this article. Common adverse events are reviewed, and management strategies for select adverse events are discussed. Implications for contemporary practitioners are also provided because use of this novel agent is likely to increase as more studies are completed.
Cabozantinib is well tolerated in acute myeloid leukemia and effectively inhibits the resistance-conferring FLT3/tyrosine kinase domain/F691 mutation. [2021]Cabozantinib, a tyrosine kinase inhibitor of FMS-like tyrosine kinase 3 (FLT3), MET, AXL, vascular endothelial growth factor receptor, and KIT, is approved for use in multiple malignancies. We assessed the safety and tolerability of cabozantinib in AML, given up-regulation of multiple relevant pathways.
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]Patients with metastatic castration-resistant prostate cancer have few treatment options after novel hormonal therapy (eg, abiraterone or enzalutamide). We aimed to evaluate cabozantinib, a tyrosine kinase inhibitor with immunomodulatory properties, in combination with the PD-L1 inhibitor atezolizumab in metastatic castration-resistant prostate cancer.
Effect of 13-cis-retinoic acid on tumor prevention, tumor growth, and metastasis in experimental colon cancer. [2019]The effect of 13-cis-retinoic acid (13-cis-RA) on 1,2-dimethylhydrazine (DMH)-induced colon cancer in male, random bred, Sprague-Dawley (S-D) and inbred Wister/Furth (W/Fu) rats and on isograft tumor growth and metastases in a Brown Norwegian (BN) X W/Fu F1 rat was studied. 13-cis-RA (300 mg/kg diet) was administered to S-D rats 1 week before commencing DMH injections and for the duration of the experiment. W/Fu rats received 13-cis-RA (10 mg/kg weight X 5 days) 6 weeks after DMH injection had begun and monthly thereafter. Primary tumors were detected by serial laparotomy under ether anesthesia in both strains. The time to tumor onset was significantly delayed in treated groups, S-D and W/Fu, P = 0.0339 and 0.0322, respectively (Mantel-Haenszel test), compared with placebo-treated controls. 13-cis-RA (15 mg/kg weight) administered 2 days before and for the duration of isograft tumor growth (DMH 2054, a well-differentiated mucin-producing colon adenocarcinoma that spontaneously metastasized to lung) had no effect on tumor growth or metastasis in the BN X W/Fu F1 rat. The findings suggest that the role of 13-cis-RA is in colon cancer prevention and not in its treatment either in an adjuvant or established setting.
13-cis-retinoic acid in chemoprevention of superficial bladder cancer. The National Bladder Cancer Group. [2013]Animal studies indicate that 13-cis-retinoic acid (CRA) inhibits bladder tumor growth and is effective in treating patients with serious dermatologic disorders. A trial of CRA in patients at high risk for recurrent Ta, T1 tumors was initiated at an experimental dose of 0.5 mg/kg/d in three divided doses, increasing to 1 mg/kg/d at four weeks. Treatment of twenty eligible patients lasted for six months with an additional 24 month follow-up period. One patient was later excluded due to toxicity resulting in an early dose reduction. Eight patients stopped treatment before three months; of these five, had recurrences within three months, one developed pulmonary metastasis, and one developed a T2G3 tumor. Four patients stopped treatment between three and six months; three of them had recurrences before one year and one had no evidence of disease at seven years. Seven patients completed the course; of these three had recurrences within six months, and three more had recurrences at 8, 15, and 45 months, respectively. Toxicity was nearly universal; cheilosis, conjunctivitis, pruritus, joint and eye pain, flashing lights, and erythrocyte sedimentation rate (ESR) over 60 were all noted. The lack of positive results and the frequency and severity of toxicity led to termination of the study.
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]Label="PURPOSE">The reported maximum tolerated dose (MTD) of single-agent belinostat is 1000 mg/m2 given days 1-5, every 21 days. Pre-clinical evidence suggests histone deacetylase inhibitors enhance retinoic acid signaling in a variety of solid tumors. We conducted a phase I study of belinostat combined with 50-100 mg/m2/day 13-cis-retinoic acid (13-cRA) in patients with advanced solid tumors.
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]The efficacy of 13-cis-retinoic acid (13-CRA) given as a single agent or in combination with tamoxifen (TAM) was determined in athymic nude mice bearing advanced s.c. MCF-7 human breast cancers.