A Phase I study of cabozantinib monotherapy in pediatric patients with recurrent and/or refractory solid tumors

JRCT ID: jRCT2031210610

Registered date:15/02/2022

Basic Information

• Recruitment status: Not Recruiting
• Health condition(s) or Problem(s) studied: Refractory pediatric solid tumor
• Date of first enrollment: 28/04/2022
• Target sample size: 18
• Study type: Interventional
• Intervention(s): The initial dose of Cabozantinib is 40mg/m2. Administer orally once daily at intervals of 12 hours or more on empty stomach according to the prescribed dose and the day of the week. One cycle is 28 days, and treatment is continued unless the protocol treatment discontinuation criteria are met.

Outcome(s)

• Primary Outcome: Assessment of the incidence of DLT-equivalent toxicities of cabozantinib monotherapy

Secondary Outcome

1)Safety endpoints: incidence rate of adverse events, Grade-4 non-hematologic toxicity, early death, incidence rate of treatment-related death and DLT-equivalent adverse events in Cohort 2.
2) Pharmacokinetic parameters: Cmax, Tmax, AUC0-24, AUC0-infinity, population pharmacokinetic parameters,
3) Efficacy endpoints: response rate, 16-week disease control rate, progression-free survival, overall survival, response rate by the cancer type, 16-week disease control rate by cancer type.

Key inclusion & exclusion criteria

• Age minimum: >= 3age old
• Age maximum: <= 19age old
• Gender: Both

Include criteria

1)Patients with a histologically confirmed malignant solid tumor. Hematological malignancies (such as leukemia, malignant lymphoma, and multiple myeloma) are not eligible.
2) Patients with any of the following conditions,
(1)A recurrent or metastatic disease or no indication for curative surgery,
(2)No standard treatment or refractoriness or intolerance to the standard therapy.
3) No evidence of the pericardial effusion, pleural effusion, or ascites requiring a treatment.
4) Age at enrollment, Cohort 1: 3-15 years; Cohort 2: 3-19 years.
5) Patients who could swallow a 5.6-mm-diameter tablet.
6) Performance status is >=50 (assessed by the KPS in patients aged >=16 years and LPS in patients aged <=15 years) within 14 days prior to the enrollment.
7) Patients must meet one of the following criteria,
(1) Patients with at least one evaluable disease on contrast-enhanced computed tomography (CT) within 28 days prior to the enrollment. CT and magnetic resonance imaging (MRI) without a contrast medium are also acceptable for patients with the extracranial diseases, who cannot use a contrast medium. However, in cases of brain tumors, a craniocerebral contrast-enhanced MRI is required, and the patient is ineligible if the contrast-enhanced MRI cannot be performed.
(2) Tumor infiltration is confirmed by the bone marrow aspiration/biopsy.
8) No history of prior administration of cabozantinib, crizotinib, or tivantinib.
9) Patients with the primary brain tumors have not received any new or increased doses of corticosteroids either intravenously or orally, between seven days prior to and on the day of the brain contrast MRI performed within the 28 days prior to the enrollment. If a new or increased dose of corticosteroid is administered between the time of a brain contrast MRI, and start of the treatment according to the protocol. The baselines brain contrast MRI must be performed again before starting the treatment, according to the protocol.
10) Patients must not have been received any antineoplastic drugs or the other investigational drugs within 28 days prior to the enrollment.
11) Patients who have not undergone a surgery with general anesthesia within 28 days prior to the enrollment.
12) Patients who have not received the radiation therapy within 14 days prior to the enrollment.
13) Laboratory tests performed within seven days prior to the enrollment must meet all the following criteria. However, the patient must not have received a granulocyte colony-stimulating factor (G-CSF) or a blood transfusion within seven days prior to the date of the blood collection. No administration of a sustained G-CSF (PEG) within 14 days prior to the blood collection. The criteria are as follows,
(1) Neutrophil count >=1000/mm3,
(2) Platelet count >=7.5x10^4/mm3,
(3) Hemoglobin >=9.0 g/dL,
(4) Albumin >= 2.8 g/dL,
(5) Aspartate aminotransferase <= 3 times the upper limit of clinical laboratory standards,
(6) Alanine transaminase <= 3 times the upper limit of clinical laboratory standards,
(7) Total bilirubin <= 1.5 times the upper limit of clinical laboratory standards,
(8) Serum creatinine <= 1.5 times the upper limit of clinical laboratory standards,
(9) Amylase and lipase <= 1.5 times the upper limit of clinical laboratory standards,
(10) Urine protein <= 1+ by a qualitative test or UP/CR <0.5g/gCre in a single voided urine sample ,
(11) PT-INR <= 1.5.
14) Transcutaneous oxygen saturation (SpO2) of >=94 % under the room air within 14 days prior to the enrollment.
15) For patients aged <=17 years, no antihypertensive medication and systolic and diastolic blood pressure below the 95th percentile of the age- and sex-specific reference values; for patients aged >=18 years, no antihypertensive medication and systolic blood pressure < 140 mmHg and diastolic blood pressure < 90 mmHg. However, in the case of patients with the primary renal malignancies, one antihypertensive medication is acceptable.
16) In the case of women of childbearing potential, the patient agrees to use a contraception from the time consent is obtained until at least 3 months (90 days) after the last dose of the study drug. In the case of lactating patients, they agree not to breastfeed from the start of the study drug administration to at least 3 months (90 days) after the last dose of the study drug administration. For males, they agree to use the contraception from the start of study drug administration until at least 3 months (90 days) after the last dose of the study drug administration.
17) Written consent to participate in the study has been obtained from the patient, if the patient is aged >=18 years, or written consent has been obtained from a surrogate, if the subject is aged <=17 years.

Exclude criteria

1)Patients with active multiple cancers. However, the following are not excluded.
(1) Completely resected basal cell carcinoma, stage I spinous cell carcinoma, intraepithelial carcinoma, intramucosal carcinoma, superficial bladder cancer,
(2) Gastrointestinal cancer that has been curatively resected by the endoscopic resection,
(3) Other cancers that have not recurred for >5 years.
2) Progressive symptomatic brain tumors and brain metastases, carcinomatous meningitis, spinal metastases requiring the radiation or surgical procedures.
3) Infectious diseases requiring a systemic treatment.
4) Patients with the active gastrointestinal ulcers.
5) Patients with an active or previous history of pneumonitis or pulmonary fibrosis diagnosed by the imaging or clinical findings.
6) Concomitant or history of a severe hypersensitivity reaction to the study drug.
7) History of an allogeneic hematopoietic stem cell transplantation.
8) Has undergone an autologous HSCT within 12 weeks prior to the enrollment.
9) Body surface area is <0.35 m2 at the time of the enrollment.
10) Positive for either HIV antibody, HTLV-1 antibody, HBs antigen, or HCV antibody. However, patients with a positive HCV antibody, but no detectable HCV-RNA are not excluded.
11) Negative for the HBs antigen, positive for HBs antibody or HBc antibody, and positive for HBV-DNA quantification.
12) Women who are pregnant, lactating, or may be pregnant.
13) Patients with a psychosis or psychiatric symptoms that interfere with the daily life and are judged to be difficult to participate in the study.
14) History of any of the followings (within 6 months prior to enrollment) or complications,
(1) Diabetes mellitus judged to be poorly controlled,
(2) Chronic congestive heart failure (New York Heart Association cardiac function classification class III or higher),
(3) History of unstable angina, angioplasty, stent grafting, or myocardial infarction,
(4) Symptomatic or arrhythmia requiring a treatment or asymptomatic sustained ventricular tachycardia (but not asymptomatic controllable atrial fibrillation),
(5) QT prolongation syndrome requiring a treatment.
15) QT corrected for HR using Fridericia's method (QTcF) interval >470 ms on 12-lead ECG performed within 14 days prior to the enrollment.
16) Patients who are judged by the investigator or sub-investigator to be unsuitable for this study.

Related Information

• Primary Sponsor: Arakawa Ayumu