Cabozantinib and Isotretinoin in Treating Children with Relapsed or Refractory Solid Tumors
This phase I trial studies the best dose and side effects of cabozantinib when given in combination with isotretinoin in treating children with solid tumors that have come back (relapsed) or do not respond to treatment (refractory). Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Isotretinoin is a drug closely related to vitamin A and it may to help stop the growth and spread of tumor cells. Giving cabozantinib and isotretinoin may work better at treating solid tumors.
- Provision of informed consent/assent from subjects or their legal guardians
- Patients must have had histologic verification of a solid tumor, including tumors of the CNS, at the time of initial diagnosis or relapse, with disease that has progressed on standard therapy, relapsed after standard therapy, or for which no standard curative therapy is known. Patients with diffuse pontine glioma are eligible without a biopsy if they have evidence of progression after radiation therapy
- Patients must have documentation of either measurable or evaluable disease within 4 weeks of onset of study therapy: * Measurable tumor on magnetic resonance imaging (MRI), computed tomography (CT) or X-ray obtained prior to study entry. Patients who appear to have residual stable tumor upon completion of frontline therapy must undergo a biopsy to document the presence of viable tumor. If the only active target lesion in patients with stable disease was previously radiated, a biopsy must be done at least 4 weeks after radiation was completed and must demonstrate viable tumor –OR-- * Evaluable disease documented by bone marrow obtained prior to study entry with tumor cells seen on routine morphology (not by neuron specific enolase [NSE] staining only) of aspirate and/or biopsy –OR-- * (For neuroblastoma patients only) Evaluable disease documented by metaiodobenzylguanidine (MIBG) scan or bone scan obtained within 4 weeks prior to study entry with positive uptake at a minimum of one site. Patients who appear to have residual stable MIBG positive lesions upon completion of frontline therapy must undergo a biopsy to document the presence of viable neuroblastoma. If the patient has only one MIBG positive lesion and that lesion was radiated, a biopsy must be done at least 4 weeks after radiation was completed and must demonstrate viable neuroblastoma * Patients whose only evidence of disease is positive cerebrospinal fluid (CSF) for tumor cells will be considered to have evaluable disease
- Performance Status – Lansky play or Karnofsky score of >= 40
- Prior Therapy: Patients must have fully recovered from the acute toxic effects (to grade 1 or better) of all prior chemotherapy, immunotherapy, or radiotherapy prior to study enrollment with the exception of hematologic parameters (absolute neutrophil count, hemoglobin, platelet count), which need to have recovered to meet eligibility criteria * Myelosuppressive chemotherapy: must have received the last dose at least 2 weeks prior to start of study therapy (4 weeks for nitrosourea therapy). This includes any cytotoxic agents given on a low dose metronomic regimen * Biologic (anti-neoplastic agent, including retinoids): must have received the last dose at least 7 days prior to start of study therapy * Monoclonal antibodies: must have received the last dose at least 7 days or 3 half-lives, whichever is longer, prior to start of study therapy * Radiation: must have received radiation (small port) at least two weeks prior to start of study therapy. Patient must have received large field radiation therapy (i.e. craniospinal, > 50% marrow space, whole abdomen) a minimum of 8 weeks prior to start of study therapy. For patients with only one site of measurable or evaluable disease, radiation must not have been given to that site unless that site has demonstrated clear progression after radiation or, a biopsy must be done at least 4 weeks after radiation was completed and must demonstrate viable tumor * A minimum of 6 weeks must have elapsed following 131I-MIBG therapy prior to start of study therapy * Stem cell transplant (SCT): Patients are eligible 12 weeks after date of autologous stem cell infusion following myeloablative therapy (timed from start of study therapy). Patients who received an autologous stem cell infusion to support non-myeloablative therapy are eligible at any time as long as they meet the hematologic and other organ function criteria for eligibility. Patients must have fully recovered from the acute toxic effects (to grade 1 or better) of the stem cell transplantation prior to study enrollment * Growth factors: All cytokines or hematopoietic growth factors must be discontinued a minimum of 7 days prior to enrollment on this protocol (14 days for long-acting growth factors)
- Steroids are permitted for control of emesis and for symptom management in patients with intracranial metastases. However, patients with known CNS disease or CNS metastases who require increasing doses of steroids are not allowed in the study. Patients MUST be on a stable or decreasing steroid dose for greater than or equal to 1 week prior to start of study therapy
- Absolute neutrophil count (ANC) >= 750/mm^3 (for patients with known bone marrow metastatic disease OR who have received at least one prior course of myeloablative therapy requiring stem cell rescue)
- Hemoglobin >= 8.0g/dL, transfusions permitted (for patients with known bone marrow metastatic disease OR who have received at least one prior course of myeloablative therapy requiring stem cell rescue)
- Platelets >= 50,000/uL, transfusion independent (no transfusions in 7 days) (for patients with known bone marrow metastatic disease OR who have received at least one prior course of myeloablative therapy requiring stem cell rescue)
- ANC >= 1000/mm^3 (for patients without bone marrow metastatic disease AND who have NOT received at least one prior course of myeloablative therapy requiring stem cell rescue)
- Hemoglobin >= 8.0g/dL, transfusions not permitted (for patients without bone marrow metastatic disease AND who have NOT received at least one prior course of myeloablative therapy requiring stem cell rescue)
- Platelets >= 100,000/uL, transfusion independent (no transfusions in 7 days) (for patients without bone marrow metastatic disease AND who have NOT received at least one prior course of myeloablative therapy requiring stem cell rescue)
- Serum creatinine =< 1.5 X institutional upper limit of normal (IULN) or creatinine clearance >= 70 ml/min/1.73m^2
- Serum calcium and/or ionized calcium and potassium must be >= institutional lower limit of normal (ILLN), chronic supplementation permitted
- Serum bilirubin =< 1.5 X IULN
- Alanine aminotransferase (ALT) =< 3 X IULN (=< 5 X IULN if patient has known metastatic/primary disease in the liver or is currently taking steroids)
- Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.5 X IULN
- Sexually active subjects (men and women) must agree to use medically accepted barrier methods of contraception (eg, male or female condom) during the course of the study and for 4 months after the last dose of study drug(s), even if oral contraceptives are also used
- Evidence of severe or uncontrolled systemic disease, or any concurrent condition which in the investigator’s opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol
- Cardiac Disease: * History of symptomatic or medically managed arrhythmia (multi-focal premature ventricular contractions [PVCs], bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) (>= National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] 4.0 grade 3) or asymptomatic sustained ventricular tachycardia. Atrial fibrillation controlled on medication is not excluded from enrolling on study therapy * Previous history of corrected QT (QTc) prolongation as a result from other medication that required discontinuation of that medication * Congenital long QT syndrome, or 1st degree relative with unexplained sudden death under 40 years of age * Presence of left bundle branch block as measured by electrocardiography (ECG) * QTc with Bazett’s correction that is unmeasurable, or >= 480 msec on screening ECG. If a patient has QTc >= 480 msec on screening ECG, the screen ECG may be repeated twice (at least 24 hours apart). The average QTc from the three screening ECGs must be < 480 msec in order for the patient to be eligible for the study * Clinically significant cardiac event such as myocardial infarction, unstable angina pectoris, transient ischemic attack (TIA), or cerebrovascular accident (CVA) within 3 months before entry; or presence of cardiac disease that, in the opinion of the investigator, increases the risk of ventricular arrhythmia * Congestive heart failure (CHF): New York Heart Association (NYHA) class III (moderate) or class IV (severe) at the time of screening
- Blood pressure > 95th percentile for age (either systolic or diastolic) or > 140/90 for patients > 18 years of age and uncontrolled by oral medication at onset of study therapy
- Women who are currently pregnant or breastfeeding. Women of childbearing potential must have a negative serum or urine pregnancy test, prior to enrolling on study. Females of childbearing potential are defined as premenopausal females capable of becoming pregnant (ie, females who have had any evidence of menses in the past 12 months, with the exception of those who had prior hysterectomy). However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, low body weight, ovarian suppression or other reasons
- Prior therapy with cabozantinib at any time
- Major surgery within 8 weeks before starting study therapy. Surgical incisions must be completely healed for at least 2 weeks before onset of study therapy. For patients who have had a minor surgical procedure such as a core needle biopsy, dental extraction, or central line placement, this must have occurred at least 7 days prior days to starting therapy
- Prior treatment with allogeneic stem cell transplantation or total body irradiation (TBI)
- Therapeutic anticoagulation with heparins, low molecular weight heparin (LMWH), or any other agents are not allowed in subjects with intracranial tumors/metastases
- Concomitant anticoagulation at therapeutic doses with oral anticoagulants (eg, warfarin, direct thrombin and factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel) in patients without primary or metastatic CNS tumors
- The subject has experienced any of the following: * Clinically-significant gastrointestinal (GI) bleeding within 6 months before the first dose of study treatment; * Any other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment
- The subject has radiographic evidence of cavitating pulmonary lesion(s) and/or the subject has tumor invading any major blood vessels
- The subject has evidence of tumor invading the GI tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of cabozantinib
- Thromboembolic event requiring therapeutic anticoagulation within 6 months of onset of study treatment (Note: subjects with a venous filter [eg, vena cava filter] are not eligible for this study)
- GI disorders particularly those associated with a high risk of perforation or fistula formation including: * Tumors invading the GI tract, active peptic ulcer disease, inflammatory bowel disease (eg, Crohn’s disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction, abdominal fistula, GI perforation, bowel obstruction, intra-abdominal abscess within 6 months before randomization
- Inability to swallow intact tablets
- Previously identified allergy or hypersensitivity to components of the study treatment formulations
- The subject requires chronic concomitant treatment with strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John’s wort)
Locations & Contacts
Trial Objectives and Outline
I. To determine the safety, dose-limiting toxicities, and maximum tolerated dose of cabozantinib s-malate (cabozantinib) in combination with isotretinoin (13-cis-retinoic acid) in patients with relapsed or refractory solid tumors including tumors of the central nervous system (CNS).
I. To assess progression-free survival (PFS) and objective tumor response rates in children with relapsed and refractory solid tumors treated with cabozantinib plus 13-cis-retinoic acid in the context of a phase I trial.
II. To evaluate the pharmacodynamics of the combination of cabozantinib and 13-cis-retinoic acid by measuring inhibition of RET phosphorylation via plasma inhibitory activity (PIA) assays.
I. To measure and compare the levels of angiogenic markers in the plasma of patients at the time of diagnosis and after treatment with cabozantinib.
II. To determine biomarkers of response to cabozantinib therapy through reverse phase protein microarray (RPPA).
OUTLINE: This is a dose-escalation study of cabozantinib s-malate.
Patients receive cabozantinib s-malate orally (PO) on days 1-28, and isotretinoin PO twice daily (BID) for 14 consecutive days. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months.
Trial Phase & Type
University of California San Diego
Peter Eric Zage
Secondary IDs NCI-2018-02497
Clinicaltrials.gov ID NCT03611595