Trial Title:
Sequential Treatment of Cabozantinib or Cabozantinib With Nivolumab for Advanced Renal Cell Carcinoma (RCC)
NCT ID:
NCT05931393
Condition:
RCC
Renal Cell Carcinoma
Conditions: Official terms:
Carcinoma
Carcinoma, Renal Cell
Nivolumab
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Sequential Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Cabozantinib 80 MG
Description:
cabozantinib 80mg daily
Arm group label:
Cohort 1: Cabozantinib Dose Escalation
Intervention type:
Drug
Intervention name:
Cabozantinib 40Mg Tab
Description:
cabozantinib 40mg daily
Arm group label:
Cohort 2: cabozantinib + nivolumab
Intervention type:
Drug
Intervention name:
Nivolumab
Description:
nivolumab 480 mg IV every 4 weeks
Arm group label:
Cohort 2: cabozantinib + nivolumab
Summary:
The goal of this clinical trial is to learn about the effects of a higher dose of
cabozantinib or the effects of cabozantinib-nivolumab combination in patients with
advanced renal cell carcinoma who have progressed on or after receiving cabozantinib
treatment. The study will have two parts or "cohorts".
- Cohort 1: cabozantinib 80mg daily
- Cohort 2: cabozantinib 40mg daily with nivolumab The cohort assignment will be
determined by investigator, based on how much cabozantinib the participant is able
to safely receive.
Detailed description:
This is a multi-center, open-label, 2 cohort, phase II study to assess the efficacy of
cabozantinib dose escalation and cabozantinib/nivolumab combination at the time of
progression on/after cabozantinib monotherapy. The study will enroll subjects with
advanced RCC (defined as locally advanced, unresectable or metastatic) who have disease
progression on/after cabozantinib monotherapy in any line of treatment
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Patients with advanced RCC (defined as locally advanced unresectable or metastatic)
of any histology who progressed on/after cabozantinib monotherapy in any line of
treatment. Patient must have cabozantinib sensitive disease (prior treatment with
cabozantinib >6 months)
2. Ability to tolerate prior cabozantinib at 60mg PO daily (for Cohort 1) or 40mg PO
daily (for Cohort 2) with manageable toxicity profile at the respective doses, at
investigator discretion
3. Prior PD-1 inhibitor/PD-L1 inhibitor allowed
4. Evidence of measurable disease per RECIST 1.1
5. For up to 5 patients opting into on-treatment biopsy in each cohort, one of the
following must be met:
1. Archival tissue confirmed to be available and obtained within 30 days of
informed consent as well as willingness to undergo an on-treatment biopsy at 12
weeks (+/- 7 days).
OR
2. Willingness to undergo a baseline biopsy prior to Cycle 1 Day1, as well as an
on-treatment biopsy at 12 weeks (+/- 7 days).
6. Age ≥ 18 at time of consent
7. ECOG performance status ≤ 2
8. Capable of understanding and complying with the protocol requirements and must have
signed the informed consent document
9. Minimum of 2 weeks washout for cabozantinib and minimum of 44 weeks or 4 half-lives
washout, whichever is shorter, for other standard or experimental anti-cancer
therapies.
10. Recovery to baseline or ≤ Grade 1 National Cancer Institute (NCI) Common Terminology
Criteria for Adverse Events (CTCAE) Version 5 from toxicities related to any prior
treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive
therapy
11. Adequate organ and marrow function, based upon meeting all of the following
laboratory criteria within 14 days before first dose of study treatment:
1. Absolute neutrophil count (ANC) ≥ 1500/µL without granulocyte
colony-stimulating factor (G-CSF) support
2. White blood cell (WBC) count ≥ 2500/µL
3. Platelets ≥ 100,000/µL without transfusion
4. Hemoglobin ≥ 9 g/dL (≥ 90 g/L) (transfusion acceptable per investigator
discretion)
5. Alanine transaminase (ALT), AST and alkaline phosphatase (ALP) ≤ 3 x ULN. ALP ≤
5x ULN with documented bone metastases
6. Total bilirubin ≤ 1.5 x ULN (for subjects with Gilbert's disease ≤ 3x ULN)
7. Serum albumin ≥ 2.8 g/dl
8. Prothrombin (PT)/international normalized ratio (INR) or partial thromboplastin
time (PTT) test < 1.3x the laboratory ULN
9. Serum creatinine ≤ 1.5x ULN or calculated creatinine clearance ≥ 40mL/min (≥
0.675mL/sec) using the Cockcroft-Gault equation:
- Males: (140 - age) x weight (kg)/(serum creatinine [mg/dL] × 72)
- Females: [(140 - age) x weight (kg)/(serum creatinine [mg/dL] × 72)] ×
0.85
10. Urine protein/creatinine ratio (UPCR) ≤1 mg/mg (≤113.2 mg/mmol), or 24h urine
protein ≤1 g
12. Sexually active fertile subjects and their partners must agree to use medically
accepted methods of contraception (e.g., barrier methods, including male condom,
female condom, or diaphragm with spermicidal gel) during the course of the study and
for 4 months after the last dose of cabozantinib and 5 months after the last dose of
nivolumab.
Should a woman become pregnant or suspect she is pregnant while participating in this
study, she should inform her treating physician immediately.
1. Female subjects are considered to be of childbearing potential unless one of the
following criteria is met:
- documented permanent sterilization (hysterectomy, bilateral salpingectomy, or
bilateral oophorectomy), or
- documented postmenopausal status (defined as 12 months of amenorrhea in a woman
> 45 years-of-age in the absence of other biological or physiological causes.
2. In addition, females < 55 years-of-age must have a serum follicle stimulating
hormone (FSH) level > 40 mIU/mL to confirm menopause.
Exclusion Criteria:
1. For Cohort 2 only, Prior prior treatment with concurrent cabozantinib/nivolumab (not
an exclusion for cohort 1).
2. Radiation therapy for bone metastasis within 2 weeks or any other radiation therapy
within 4 weeks before first dose of study treatment. Systemic treatment with
radionuclides within 6 weeks before first dose of study treatment. Subjects with
clinically relevant ongoing complications from prior radiation therapy are not
eligible
3. Known brain metastases or cranial epidural disease unless adequately treated with
radiotherapy and/or surgery (including radiosurgery) and stable for 1) at least 2
weeks after radiotherapy or 2) at least 4 weeks after major surgery (e.g., removal
or biopsy of brain metastasis) prior to first dose of study treatment. Subjects must
have complete wound healing from major surgery or minor surgery before first dose of
study treatment. Eligible subjects must be neurologically asymptomatic and without
corticosteroid treatment for the brain metastasis at the time of first dose of study
treatment
4. Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin
inhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or platelet
inhibitors (e.g., clopidogrel). Allowed anticoagulants are the following: 1)
prophylactic use of low-dose aspirin for cardio-protection (per local applicable
guidelines) and low-dose low molecular weight heparins (LMWH). 2) Therapeutic doses
of LMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban,
or apixaban in subjects without known brain metastases who are on a stable dose of
the anticoagulant for at least 1 week before first dose of study treatment without
clinically significant hemorrhagic complications from the anticoagulation regimen or
the tumor
5. Administration of a live, attenuated vaccine within 30 days before first dose of
study treatment
6. The subject has uncontrolled, significant intercurrent or recent illness including,
but not limited to, the following conditions:
1. Cardiovascular disorders: 1) congestive heart failure New York Heart
Association Class 3 or 4, unstable angina pectoris, serious cardiac
arrhythmias; 2) uncontrolled hypertension defined as sustained blood pressure
(BP) > 140 mm Hg systolic or > 90 mm Hg diastolic despite optimal
antihypertensive treatment within 1 week of treatment; 3) stroke (including
transient ischemic attack [TIA]), myocardial infarction (MI), or other ischemic
event, or thromboembolic event (e.g., deep venous thrombosis [DVT], pulmonary
embolism [PE]) within 6 months before first dose of study treatment. Note:
subjects with a diagnosis of incidental, subsegmental PE or DVT within 6 months
are allowed if stable, asymptomatic, and treated with a stable dose of
permitted anticoagulation (see exclusion criterion #3.2.4) for at least 1 week
before first dose of study treatment
2. Gastrointestinal (GI) disorders including those associated with a high risk of
perforation or fistula formation, including 1) the subject has evidence of
tumor invading the GI tract, active peptic ulcer disease, inflammatory bowel
disease (e.g., Crohn's disease), diverticulitis, cholecystitis, symptomatic
cholangitis or appendicitis, acute pancreatitis, acute obstruction of the
pancreatic duct or common bile duct, or gastric outlet obstruction; 2)
abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal
abscess within 6 months before first dose of study treatment. Note: Complete
healing of an intra-abdominal abscess must be confirmed before first dose of
study treatment
7. Clinically significant hematuria, hematemesis, hemoptysis, or other history of
significant bleeding (e.g., pulmonary hemorrhage) within 6 weeks before first dose
of study treatment. (Clinically significant hematuria defined by needing
transfusion; clinically significant hematemesis or hemoptysis defined by needing
hospital admission)
8. Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease
manifestation
9. Lesions invading or encasing any major blood vessels
10. Other clinically significant disorders that would preclude safe study participation
1. Any active, known or suspected autoimmune disease will be excluded, with the
following exceptions: type 1 diabetes mellitus, hypothyroidism only requiring
hormone replacement, skin disorders (e.g., vitiligo, psoriasis, or alopecia)
not requiring systemic treatment, conditions not expected to recur in the
absence of an external trigger
2. Any condition requiring systemic treatment with either corticosteroids (> 10 mg
daily prednisone equivalent) or other immunosuppressive medications within 14
days before first dose of study treatment. Note: Inhaled, intranasal,
intra-articular, or topical steroids are permitted. Adrenal replacement steroid
doses > 10 mg daily prednisone equivalent are permitted. Transient short-term
use of systemic corticosteroids for allergic conditions (e.g., contrast
allergy) is also allowed
3. Active infection requiring systemic treatment. Acute or chronic hepatitis B or
C infection, known human immunodeficiency virus (HIV) or acquired
immunodeficiency syndrome (AIDS)-related illness, or known positive test for
tuberculosis infection where there is clinical or radiographic evidence of
active mycobacterial infection
4. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced
pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on
screening chest CT scan
5. Serious non-healing wound/ulcer/bone fracture
6. Malabsorption syndrome
7. Uncompensated/symptomatic hypothyroidism
8. Moderate to severe hepatic impairment (Child-Pugh B or C).
9. Requirement for hemodialysis or peritoneal dialysis
10. History of solid organ or allogenic stem cell transplant
11. Acute COVID-19 infection - clinical recovery from COVID-19 infection at least
14 days prior to enrollment allowed.
11. Major surgery (e.g., laparoscopic nephrectomy, GI surgery, removal or biopsy of
brain metastasis) within 2 weeks before first dose of study treatment. Minor
surgeries within 10 days before first dose of study treatment. Subjects must have
complete wound healing from major surgery or minor surgery before first dose of
study treatment. Subjects with clinically relevant ongoing complications from prior
surgery are not eligible
12. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per
electrocardiogram (ECG) within 14 days before first dose of study treatment.
Furthermore, subjects with a history of additional risk factors for torsades de
pointes (e.g., long QT syndrome) are also excluded. Note: If a single ECG shows a
QTcF with an absolute value > 500 ms, two additional ECGs at intervals of
approximately 3 min must be performed within 30 min after the initial ECG, and the
average of these three consecutive results for QTcF will be used to determine
eligibility.
13. Pregnant or lactating females
14. Inability to swallow tablets
15. Cohort 2: Unwillingness or inability to receive intravenous (IV) administration
16. Previously identified allergy or hypersensitivity to components of the study
treatment formulations or history of severe infusion-related reactions to monoclonal
antibodies. Subjects with rare hereditary problems of galactose intolerance, the
Lapp lactase deficiency or glucose-galactose malabsorption are also excluded
17. Another malignancy within 2 years prior to first dose of study treatment that
requires active treatment, except for locally curable cancers that have been
apparently cured, such as basal or squamous cell skin cancer, superficial bladder
cancer, Gleason 6 prostate cancer, or carcinoma in situ of cervix or breast
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
UT Southwestern Medical Center
Address:
City:
Dallas
Zip:
75390
Country:
United States
Status:
Recruiting
Investigator:
Last name:
Tian Zhang, MD
Email:
Principal Investigator
Start date:
December 20, 2023
Completion date:
December 31, 2027
Lead sponsor:
Agency:
University of Texas Southwestern Medical Center
Agency class:
Other
Collaborator:
Agency:
Exelixis
Agency class:
Industry
Source:
University of Texas Southwestern Medical Center
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05931393
