Trial Title:
A Study of Combining Cabozantinib and Atezolizumab for Advanced/Metastatic NSCLC (Cabatezo-1)
NCT ID:
NCT05859217
Condition:
Lung Cancer
NSCLC Stage IV
Metastatic NSCLC - Non-Small Cell Lung Cancer
Advanced NSCLC
Conditions: Official terms:
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Atezolizumab
Conditions: Keywords:
Cancer immunotherapy
anti-angiogenesis
Investigator-initiated clinical trial
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Cabozantinib
Description:
Oral once per day, Days 1 - 21 every 21 days
Arm group label:
Cabozantinib and Atezolizumab
Other name:
Cabometyx
Intervention type:
Drug
Intervention name:
Atezolizumab
Description:
Intravenous (IV) once every 21 days
Arm group label:
Cabozantinib and Atezolizumab
Other name:
Tecentriq
Summary:
NSCLC patients with low expression level of PD-L1, esp. those with its level less than
1%, do not derive much benefit from anti-PD-1/L1 therapy (e.g. atezoilzumab). In this
study, investigators hypothesize that the combination of cabozantinib (a multi-kinase
inhibitor) and atezolizumab will result in better therapeutic value.
Detailed description:
For metastatic/advanced non-small cell (NSCLC) patients who do not have targetable
mutations, the combination of chemotherapy with immunotherapy targeting the programmed
death-1 and its ligand (PD-1/L1) is now a standard of care. In addition, recent studies
also demonstrated that immunotherapy doublet using anti-PD-1 agent nivolumab and
anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) agent ipilimumab could be
another valid option. However, largely due to the immunosuppressive tumor
microenvironment, the therapeutic response remains suboptimal in NSCLC patients with
PD-L1 tumor proportion score (TPS) lower than 1% (aka PD-L1 negative). For example, the
objective response rate (ORR) in KEYNOTE-189 was 32.3% using pembrolizumab plus
chemotherapy, and only 27.3% in Checkmate 227 study using nivolumab and ipilimumab, in
the PD-L1 negative population. These observations necessitate the search for novel
combinations to benefit our PD-L1 negative NSCLC patients.
The investigators hypothesize that the combination of cabozantinib and atezolizumab is
such an innovative strategy based on the following rationales: 1) cabozantinib is a
multi-kinase inhibitor, and some of the targets, for example the vascular endothelial
growth factor (VEGF) pathway is notorious to confer immune suppressive tumor
microenvironment. In fact, our previous study has demonstrated that anti-VEGF synergizes
anti-PD-1 in preclinical model. Consistent with this, cabozantinib has been shown to
increase tumor infiltrative cytotoxic CD8+ T cells, reduce immune suppressive T
regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs), as well as
activate anti-tumor innate immunity in multiple solid tumors; 2) at the animal level,
cabozantinib was found synergistic with anti-PD-1 agents to elicit anti-tumor immune
response; and 3) more importantly, at the human level, the combination of cabozantinib
with atezolizumab was found safe in Cohort 7 of the phase 1b COSMIC-021 study and
achieved 27% ORR in previously immunotherapy-treated NSCLC - suggesting a potentially
higher efficacy if such combination is to be used in the 1st line setting.
The investigators therefore propose here the combination of cabozantinib and atezolizumab
to be used as the 1st line treatment for advanced/metastatic NSCLC with negative PD-L1
expression.
Criteria for eligibility:
Criteria:
INCLUSION CRITERIA:
- Ability of participant OR Legally Authorized Representative (LAR) to understand this
study, and participant or LAR willingness to sign a written informed consent
- Males and females age ≥ 18 years
- ECOG Performance Status 0 - 1
- Pathologically confirmed advanced/metastatic NSCLC, with PD-L1<1% based on IHC using
22C3 antibody
- At least one target lesion that can be assessed by RECIST 1.1
- For candidates who are not qualified for upfront FDA-approved targeted therapy, must
be systemic treatment naïve (local palliative RT more than 4 weeks prior is allowed)
- For candidates who are qualified for upfront FDA-approved targeted therapy (e.g.
having sensitizing mutations in EGFR, ALK and BRAF, etc.), treatment must have
failed and received at least one line of ONLY FDA-approved targeted therapy
- Availability of a representative tumor specimen for correlative research. Optional
but highly recommended: willing to undergo tumor tissue biopsy only if deemed safe
and feasible by the investigator.
- Recovery to baseline or ≤ Grade 1 CTCAE v5 from toxicities related to any prior
treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive
therapy.
- Women of childbearing potential must have a negative serum pregnancy test 72 hours
prior to initiating treatment. Female participants 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. In addition, females < 55 years-of-age must have a serum
follicle stimulating (FSH) level > 40 mIU/mL to confirm menopause). Note:
Documentation may include review of medical records, medical examinations, or
medical history interview by study site.
- Women of child-bearing potential and men with partners of child-bearing potential
must agree to practice sexual abstinence or to use two forms of adequate
contraception (hormonal AND barrier method of birth control) prior to study entry,
for the duration of study participation and for 6 months following completion of
therapy.
- Men of child-bearing potential must not father a child or donate sperm while on this
study and for 6 months after the last study treatment.
- Adequate organ function
- Negative HIV test at screening, with the following exception: patients with a
positive HIV test at screening are eligible provided they are stable on
anti-retroviral therapy, have a CD4 count >200/uL, and have an undetectable viral
load. They must agree to continue on such anti-retroviral therapy per local standard
treatment guideline
- Negative HBV and HCV tests at screening, with the following exception:
- For HBV: DNA must be < 500 IU/mL (or must be < 2500 copy/mL if copy/mL is the
only unit available in the study site; if the normal ranges of the study sites
are different, the positive standard must not be met), and have received
anti-HBV therapy for at least 14 days prior to the first dose of study
treatment (treatment in accordance with local standard of care, e.g.,
entecavir) and are willing to receive antiviral therapy throughout the study if
indicated;
- For HCV (with positive HCV RNA): must receive anti-viral therapy in accordance
with the local standard treatment guideline and hepatic function resolve to
CTCAE Grade ≤1
EXCLUSION CRITERIA:
- Simultaneously enrolled in any therapeutic clinical trial
- Current or anticipating use of other investigational agents while participating in
this study
- Treatment with investigational therapy within 28 days prior to initiation of study
treatment
- Diagnosed with a psychiatric illness or is in a social situation that would limit
compliance with study requirements
- Active Grade 3 (per the NCI CTCAE, Version 5.0) or higher viral, bacterial, or
fungal infection within 2 weeks prior to the first dose of study treatment
- Patients harboring targetable mutations (e.g., EGFR, ALK and BRAF, etc.) who have
not had at least one frontline targeted therapy fail, or have received other
systemic therapies (e.g. chemotherapy, immunotherapy, etc.)
- Patients with carcinomatous meningitis (leptomeningeal metastasis)
- Undergone major surgery within 2 weeks prior to the start of study regimen, or has
not achieved complete wound healing
- Presence of another cancer with disease manifestations or therapy that could
adversely affect participant safety or longevity, create the potential for drug-drug
interactions, or compromise the interpretation of study results. Otherwise, patients
can be considered eligible, for example, locally curable cancers that have been
apparently cured, such as basal or squamous cell skin cancer, superficial bladder
cancer, or carcinoma in situ of the prostate, cervix, or breast.
- Prior treatment with cabozantinib and/or atezolizumab.
- Receipt of any type of small molecule kinase inhibitor (including investigational
kinase inhibitor) within 2 weeks before first dose of study treatment.
- Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy
(including investigational) within 4 weeks before first dose of study treatment
- Radiation therapy within 4 weeks before first dose of study treatment. Systemic
treatment with radionuclides within 6 weeks before first dose of study treatment.
Participants with clinically relevant ongoing complications from prior radiation
therapy are not eligible.
- Known brain metastases or cranial epidural disease unless adequately treated with
radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks
prior to first dose of study treatment after radiotherapy or at least 4 weeks prior
to first dose of study treatment after major surgery (e.g., removal or biopsy of
brain metastasis). Participants must have complete wound healing from major surgery
or minor surgery before first dose of study treatment. Eligible participants must be
neurologically asymptomatic and with corticosteroid no more than 10mg prednisone or
equivalent at the time of first dose of study treatment.
- 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:
- Prophylactic use of low-dose aspirin for cardio-protection (per local
applicable guidelines) and low-dose low molecular weight heparins (LMWH).
- Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors
such as rivaroxaban, edoxaban, or apixaban in participants 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.
- Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to
initiation of study treatment, during treatment with atezolizumab, and for 5 months
after the last dose of atezolizumab.
- The participant has uncontrolled, significant cardiovascular disorders
- Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5
ml) of red blood, or other history of significant bleeding (e.g., pulmonary
hemorrhage) within 12 weeks before first dose of study treatment
- Lesions invading or encasing any major blood vessels.
- Other clinically significant disorders that would preclude safe study participation
- 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. Participants must
have complete wound healing from major surgery or minor surgery before first dose of
study treatment. Participants with clinically relevant ongoing complications from
prior surgery are not eligible
- Pregnant or lactating females.
- Inability to swallow tablets or unwillingness or inability to receive IV
administration.
- Previously identified allergy or hypersensitivity to Chinese hamster ovary cell
products, or components of the study treatment formulations or history of severe
infusion-related reactions to monoclonal antibodies.
- Uncontrolled tumor-related pain
- Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
drainage procedures (once monthly or more frequently). Patients with indwelling
catheters (e.g., PleurX) are allowed.
- Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium >
12 mg/dL or corrected serum calcium > ULN)
- Active or history of autoimmune disease or immune deficiency (see Appendix I),
including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis,
systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease,
antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome,
Guillain-Barré syndrome, or multiple sclerosis.
- Severe infection within 4 weeks prior to initiation of study treatment, including,
but not limited to, hospitalization for complications of infection, bacteremia, or
severe pneumonia
- Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation
of study treatment. Patients receiving prophylactic antibiotics (e.g., to prevent a
urinary tract infection or chronic obstructive pulmonary disease exacerbation) are
eligible for the study.
- Prior treatment with CD137 agonists or immune checkpoint blockade therapies,
including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
- Treatment with systemic immunostimulatory agents (including, but not limited to,
interferon and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug
(whichever is longer) prior to initiation of study treatment
- Any serious illness, uncontrolled inter-current illness, psychiatric illness, active
or uncontrolled infection, or other medical history, including laboratory results,
which, in the Investigator's opinion, would be likely to interfere with the
patient's participation in the study, or with the interpretation of the results
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
The University of Kansas Cancer Center - Westwood
Address:
City:
Kansas City
Zip:
66205
Country:
United States
Contact:
Last name:
Clinical Trial Nurse Navigator
Phone:
913-945-7552
Email:
ctnursenav@kumc.edu
Facility:
Name:
The University of Kansas Cancer Center - Indian Creek
Address:
City:
Overland Park
Zip:
66211
Country:
United States
Facility:
Name:
The University of Kansas Cancer Center - North
Address:
City:
Kansas City
Zip:
64154
Country:
United States
Contact:
Last name:
Clinical Trial Nurse Navigator
Phone:
913-945-7552
Email:
ctnursenav@kumc.edu
Facility:
Name:
The University of Kansas Cancer Center - Lee's Summit
Address:
City:
Lee's Summit
Zip:
64064
Country:
United States
Contact:
Last name:
Clinical Trial Nurse Navigator
Phone:
913-945-7552
Email:
ctnursenav@kumc.edu
Start date:
December 2024
Completion date:
June 2028
Lead sponsor:
Agency:
Jun Zhang, MD, PhD
Agency class:
Other
Collaborator:
Agency:
Exelixis
Agency class:
Industry
Collaborator:
Agency:
Genentech, Inc.
Agency class:
Industry
Source:
University of Kansas Medical Center
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05859217
