Dose-Escalation Stage (Combination Therapy Cohorts):The primary objective is as follows:• To determine the maximum tolerated dose (MTD) and/or recommended dose and schedule for the subsequent Expansion Stage of daily oral administration of…
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- Renal and urinary tract neoplasms malignant and unspecified
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Research involving
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Intervention
Outcome measures
Primary outcome
SAFETY ASSESSMENTS
Safety evaluations will include assessments of AEs (including irAEs and AESIs),
vital signs, ECGs, laboratory tests, and concomitant medications. Adverse event
seriousness, severity grade, relationship to study treatment, and relationship
to immune effects (ie, irAEs) will be assessed by the investigator. Severity
grade will be defined by the NCI CTCAE version 4.
TUMOR ASSESSMENTS
Tumor response will be assessed using RECIST 1.1 (Appendix G). Additional
exploratory efficacy evaluation will include the application of irRECIST for
immune response (Appendix H). Subjects will be assessed using a magnetic
resonance imaging (MRI) or a CT scan from the date of the first dose of study
treatment until the later of radiographic disease progression per RECIST 1.1 as
determined by the investigator or the date of the decision to permanently
discontinue study treatment. Radiographic tumor assessments will continue on
the protocol-defined schedule, regardless of whether study treatment is
reduced, interrupted, delayed, or discontinued.
Chest / Abdomen / Pelvis/ Neck: Unless otherwise described, CT of
Chest/Abdomen/Pelvis (CAP) or CT chest and MRI abdomen/pelvis will be performed
in all subjects at screening and every 6 weeks (± 5 days) after initiation of
study treatment throughout the first 12 months on study. Upon completion of 12
months on study, these assessments will be performed every 12 weeks (± 7 days).
For subjects with DTC and head & neck cancer, CT/MRI of the neck will be
performed in addition to the CAP assessments. Subjects with head & neck cancer
will be using the same imaging schedule after screening. For subjects with DTC
the imaging frequency after screening will be every 9 weeks after initiation of
study treatment throughout the first 12 months on study; upon completion of 12
months on study, these assessments will be performed every 12 weeks (± 7 days).
Low dose non-contrast CT images from combined positron emission
tomography/computed tomography (PET/CT) imaging cannot be used for tumor
evaluations in this study.
Brain: MRI (or CT) of the brain will be performed at screening in all subjects
with RCC, head and neck cancer, and NSCLC and for subjects with the other tumor
indications who have a history or clinical symptoms of brain metastasis. After
study treatment initiation MRI (or CT) scans of the brain are only required in
subjects with documented, treated brain metastasis or if clinically indicated
by signs and symptoms suggestive of new central nervous system (CNS)
metastases. Assessments after the first dose of study treatment will be
performed every 12 weeks (± 7 days). MRI is the preferred imaging method for
brain. If CT of the brain is performed instead of MRI, ambiguous results must
be confirmed by MRI unless contraindicated. Subjects without documented brain
metastasis during the screening assessment are not required to undergo brain
imaging after initiating study treatment unless clinically indicated. In order
to meet the eligibility requirements of the study, brain metastasis must have
been treated and stable for at least 4 weeks before first dose of study
treatment.
Bone scans: Technetium bone scans (TBS) will be performed at screening in all
subjects with CRPC and for subjects with the other tumor indications who have a
history or clinical symptoms (ie, bone pain) of bone metastases. After study
treatment initiation bone scans are only required in subjects with documented
bone lesions or if clinically indicated by signs and symptoms suggestive of new
bone metastases. Assessments after the first dose will follow routine clinical
practice (approximately every 12 weeks throughout the first 12 months and every
24 weeks thereafter). Lesions identified on bone scan are not to be recorded as
target, non-target, or new lesions. Bone scan findings alone cannot be used for
the determination of progression or response in this study and need to be
corroborated by CT/MRI. Bone lesions corroborated by CT/MRI must be reported as
non-target or new lesions. PET scan or plain films are not considered adequate
imaging techniques to measure bone lesions.
Subjects enrolled in the SAC or SAA cohorts who experience
Investigator-assessed radiographic progression per RECIST 1.1 may be eligible
to receive the combination therapy in the Second Agent Add-On Stage (see
Section 3.5.2.4 for more details). A new baseline tumor status will be
established for these subjects based upon their most recent set of scans
performed prior to receiving the first dose of the second agent in the Second
Agent Add-On Stage; if these scans were taken > 4 weeks prior to first dose of
the second agent, new scans will be required to establish the baseline.
For the purpose of determining radiographic study endpoints for selected
cohorts, central review of radiographic images may be conducted by a BIRC. All
protocol-required radiographic tumor assessments for these selected cohorts
will be sent to the BIRC, which also will review prior radiation history data
and prior local therapy information for the purpose of selection of target
lesions. Details are provided in the Imaging Manual.
TUMOR MARKER ASSESSMENTS
For subjects with CRPC, HCC, OC, CRC, and DTC, tumor marker samples (ie, PSA,
alpha-feta protein [AFP], CA125, carcinoembryonic antigen [CEA], and
thyroglobulin, respectively) will be collected at screening, Day 1 of every
third cycle (or every 9 weeks, whichever is earlier) for the first 12 months on
study, and then Day 1 of every fifth cycle (or every 15 weeks, whichever is
earlier) until the earlier of initiation of subsequent systemic anticancer
therapy or permanent loss to radiographic follow-up (including hospice
admission). For subjects with CRPC who receive combination treatment in the
Second Agent Add-On Stage, PSA samples will be collected at screening for that
stage, Day 1 of every third cycle on that stage (or every 9 weeks, whichever is
earlier) for the first 12 months, and then Day 1 of every fifth cycle of that
stage (or every 15 weeks, whichever is earlier) until the earlier of initiation
of subsequent systemic anticancer therapy or permanent loss to radiographic
follow-up (including hospice admission). The tumor marker assessments will not
be used to determine progressive disease or to make study treatment decisions
in this study.
OVERALL SURVIVAL FOLLOW-UP ASSESSMENTS
Subjects will be contacted (eg, in person or by telephone) approximately every
12 weeks (± 14 days) after the Post Treatment Follow-Up Visit to assess
survival status and to document receipt of subsequent anticancer therapy unless
consent to participate in survival follow-up is withdrawn or the Sponsor deems
sufficient efficacy data have been collected for the study.
PHARMACOKINETIC ASSESSMENTS
Dose-Escalation Stage:
Blood samples for PK analysis will be obtained on the date of first dose of
study treatment (C1D1; prior to study treatment administration [cabozantinib
and atezolizumab], approximately 5 min after completion of the atezolizumab
infusion, and at 2 h, 4 h, and 6-8 h after cabozantinib dosing), and prior to
study treatment dosing on C1D10, C2D1, and C3D1.
Expansion Stage:
Combination Therapy Expansion Cohorts:
Blood samples for PK analysis will be obtained for plasma cabozantinib and
serum atezolizumab concentration measurement on the date of first dose of study
treatment (C1D1; prior to study treatment administration [cabozantinib and
atezolizumab], approximately 5 min after completion of the atezolizumab
infusion, and 2 h after the first dose of cabozantinib) and prior to study
treatment dosing (atezolizumab infusion) on C2D1 and C3D1.
Exploratory SAC Cohorts:
Blood samples for PK analysis will be obtained for plasma cabozantinib on the
date of first dose of cabozantinib treatment (C1D1; prior to cabozantinib
treatment administration) and on C2D1 and C3D1.
Exploratory SAA Cohort:
Blood samples for PK analysis will be obtained for serum atezolizumab
concentration measurement on the date of first dose of study treatment (C1D1;
prior to study treatment administration, approximately 5 min after completion
of the atezolizumab infusion) and prior to study treatment dosing on C2D1 and
C3D1.
In the Dose-Escalation Stage and for the Combination-Therapy Cohorts in the
Expansion Stage, samples will be analyzed for the plasma concentration of
cabozantinib and the serum concentrations of atezolizumab. Only the PK of
cabozantinib will be assessed for subjects in the SAC Cohorts, and only the PK
of atezolizumab will be assessed for subjects in the SAA Cohort. PK will not be
assessed in subjects who receive combination therapy after progression on
single agent therapy (Second Agent Add-On Stage).
IMMUNOGENICITY ASSESSMENTS
Blood samples will be obtained from all subjects in the combination treatment
cohorts and subjects in the Exploratory SAA Cohort in the Expansion Stage for
immunogenicity assessment predose on C1D1, C3D1, C7D1, and at the
Post-Treatment Follow-up Visit. For subjects who radiographically progress per
RECIST 1.1 on single-agent therapy in the SAC Cohorts and transition to
combination therapy, blood samples for immunogenicity assessments will be
collected predose on Add on Cycle 1 Day 1 (aoC1D1), aoC3D1, and aoC7D1 in the
Second Agent Add-On Stage and at the Post Treatment Follow-up Visit. For
subjects who radiographically progress per RECIST 1.1 on single-agent therapy
in the SAA Cohort and transition to combination therapy, a blood sample for
immunogenicity assessment will be collected at the Post Treatment Follow-up
Visit.
BIOMARKER ASSESSMENTS
Peripheral blood and tumor tissue will be collected and may be assessed for
exploratory biomarker analyses. Peripheral blood samples will be obtained as
specified in the Schedule of Assessments. Tumor tissue (archival) will be
obtained prior to first dose of study treatment, and optional fresh tumor
tissue biopsies may also be performed. Exploratory analyses may include the
following:
• MET, AXL, and PD-L1 in tumor specimens for association with clinical outcomes
• Immune cell infiltration and tumor characteristics (ie, mutational load
assessment) in tumor specimens and blood for association with clinical outcome
• Circulating immune cells in peripheral blood (ie, lymphocyte subset analyses
by flow cytometry)
• Blood biomarkers (ie, cytokines/chemokines, VEGF)
• Evaluation of MMR and MSI status
Collection of biomarker samples may be halted early or sampling frequency may
be modified at the discretion of the Sponsor.
For NSCLC subjects, available tumor mutation analysis reports (indicating EGFR
status) should be provided at screening. For eligibility review for Expansion
Cohort 8, prior PD-L1 reports from tests using the FDA approved pharmDx PD L1
22C3 kits should be provided early in screening.
Secondary outcome
For parameters/outcome, please see above.
Background summary
Multi-targeted tyrosine kinase inhibitors (TKIs) and immune checkpoint
inhibitors (ICIs) represent two systemic modalities that have been instrumental
in the recent advancements of anticancer treatment over the past several years.
Both classes of therapies have demonstrated broad clinical effects leading to
new approved treatment options across multiple tumor types. The success of
these therapy types as single agents with distinct mechanisms of action has
naturally led to interest in evaluating combinations of TKIs with ICIs in
search of further, possibly synergistic, anticancer clinical effects.
Atezolizumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody that
targets programmed death receptor 1 ligand (PD L1) and inhibits the interaction
between PD-L1 and its receptors, programmed death receptor 1 (PD-1) and B7-1
(also known as CD80), both of which function as inhibitory receptors expressed
on T cells. Atezolizumab injection for intravenous (IV) use (1200 mg once every
3 weeks [q3w]) has been approved in the US and EU for the treatment of adult
patients with advanced urothelial carcinoma (UC) after prior platinum
containing chemotherapy or in a subset of patients who are considered
cisplatin-ineligible (different patient populations are indicated depending on
region; Rosenberg et al 2016, Balar et al 2017). Atezolizumab in combination
with bevacizumab, paclitaxel, and carboplatin has been approved in the US for
the first line treatment of adult patients with metastatic non-squamous
non-small cell lung cancer (NSCLC) with no epidermal growth factor receptor
(EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations.
Atezolizumab is also approved for adult patients with locally advanced or
metastatic NSCLC after prior chemotherapy (Fehrenbacher et al 2016; Tecentriq*
US prescribing information [US PI] and European Medicines Agency Summary of
Product Characteristics [EMA SmPC]). Recently, atezolizumab was also granted
accelerated approval in the US for treatment in combination with paclitaxel
protein bound (nab-paclitaxel) for adult patients with unresectable locally
advanced or metastatic triple negative breast cancer (TNBC) whose tumors
express PD-L1 (Schmid et al 2018) and was also approved for first-line
treatment in combination with carboplatin and etoposide in adult patients with
extensive-stage small cell lung cancer (ES-SCLC; Horn et al 2018, Tecentriq US
PI). Treatment with atezolizumab is generally well-tolerated but can be
associated with immune-related adverse events (irAEs).
Further, atezolizumab has demonstrated encouraging clinical activity in other
tumor treatment settings: monotherapy in treatment-naïve advanced-stage NSCLC
(Peters et al 2017), combination with chemotherapy and bevacizumab in
treatment-naive advanced-stage NSCLC (Sociniski et al 2018), monotherapy in
advanced renal cell carcinoma (RCC) (McDermott et al 2016), monotherapy in
metastatic castration-resistant prostate cancer (mCRPC; Kim et al 2018),
combination with bevacizumab in treatment-naïve advanced RCC (Motzer et al
2018), monotherapy in advanced triple-negative breast cancer (TNBC; Schmid et
al 2017), monotherapy in advanced ovarian cancer (OC; Infante et al 2016),
monotherapy in advanced endometrial cancer (EC; Fleming et al 2017),
monotherapy and combination with bevacizumab in treatment-naïve hepatocellular
carcinoma (HCC; Stein et al 2018; Roche data on file), monotherapy in advanced
gastric cancer (GC; Taieb et al 2018), combination with bevacizumab (±
chemotherapy) in advanced colorectal cancer (CRC; Hochster et al 2017), and
monotherapy in advanced head and neck (H & N) cancer (Bahleda et al 2017). In
addition, atezolizumab is currently being evaluated in combination with
bevacizumab or molecular targeted therapies in anaplastic and differentiated
thyroid cancer (NCT03181100).
Cabozantinib (XL184) is a potent inhibitor of multiple receptor tyrosine
kinases (RTKs) known to play important roles in tumor cell proliferation and/or
tumor neovascularization including MET, vascular endothelial growth factor
receptor (VEGFR), AXL, and RET. Increased expression of MET and AXL has been
implicated in the development of resistance to VEGFR inhibitors in preclinical
models of several cancers (Shojaei et al 2010, Zhou et al 2016, Sennino et al
2012, Ciamporcero et al 2015). In addition, targets of cabozantinib are
implicated in promoting tumor immune suppression including TYRO3, MER, and AXL
(tumor-assisted macrophage [TAM] family kinases).
Cabozantinib capsules (140 mg) are approved in the US for the treatment of
patients with progressive, metastatic medullary thyroid cancer (MTC) and in the
EU for the treatment of patients with progressive, unresectable locally
advanced or metastatic MTC (Cometriq® US PI and EMA SmPC). Cabozantinib tablets
(60 mg) are approved in the US, Europe, and other regions for advanced RCC
(different patient populations depending on region; Cabometyx® US PI and EMA
SmPC). Based on the results from a randomized placebo-controlled Phase 3 study
(CELESTIAL) in subjects who had received prior sorafenib, cabozantinib tablets
(60 mg) as a single agent have also been approved in the US, EU, and other
regions for an HCC indication (Cabometyx US PI and EMA SmPC).
Cabozantinib has also demonstrated encouraging clinical activity in other tumor
indications: monotherapy in advanced urothelial carcinoma (Apolo et al [J Clin
Oncol] 2016), in combination with ICIs in advanced urothelial carcinoma (Nadal
et al 2018, Nadal et al 2017, Apolo et al [Ann Oncol] 2016), monotherapy in
CRPC (Smith et al 2013, Smith et al 2014, Basch et al 2015), monotherapy or in
combination with erlotinib in advanced NSCLC (Schöffski et al 2017, Neal et al
2016), monotherapy in RET-rearranged NSCLC (Drilon et al 2016), monotherapy in
advanced TNBC (Tolaney et al 2017), monotherapy in advanced OC (Matulonis et al
2016, Vergote et al 2017), monotherapy in advanced EC (Dhani et al 2017;
Mandilaras et al 2017), monotherapy in advanced GC (Schöffski et al 2017), in
combination with panitumumab in CRC (Strickler et al 2016), and monotherapy in
radioactive-iodine refractory DTC (Brose et al 2018, Cabanillas et al 2014,
Cabanillas et al 2017).
Preclinical studies (Kwilas et al 2014, Song et al 2015, Lu et al 2017) and
clinical observations on circulating immune suppressive cells and immune
effector cells (Apolo et al 2014) suggest that cabozantinib promotes an
immune-permissive environment through inhibition of immune-modulatory targets
on immune cells. This might present an opportunity for synergistic effects from
combination treatment with ICIs. The combination of cabozantinib with ICIs may
also provide a strategy to overcome resistance to ICI therapy. This is based on
recent observations in clinical trials where re-treatment with an ICI in
combination with cabozantinib or a VEGFR-TKI that has a target profile similar
to cabozantinib resulted in reversal of prior ICI resistance in advanced UC and
NSCLC patients (Nadal et al 2018, Leal et al 2017). These results suggest that
combining ICIs with cabozantinib may result in a tumor microenvironment that is
conducive to re-sensitization to ICI therapy after prior progression on an ICI.
In this Phase 1b study, a total of 12 subjects with advanced RCC were enrolled
in the Dose-Escalation Stage using a 3 + 3 design. Six (6) subjects were
evaluated at both the 40-mg and 60-mg cabozantinib dose levels in combination
with the standard dose of atezolizumab. Both dose levels of cabozantinib were
generally well tolerated, and no dose limiting toxicities (DLTs) were observed.
After reviewing all available safety and efficacy data of the Dose Escalation
Stage, the Cohort Review Committee determined that cabozantinib 40 mg qd orally
in combination with 1200 mg atezolizumab q3w IV is the recommended dose for the
Expansion-Stage combination-therapy cohorts. The Cohort Review Committee
decision was based on the favorable safety profile of the 40-mg cabozantinib
dose level over a prolonged time on study treatment with less frequent dose
reductions and encouraging preliminary efficacy, which was deemed to optimize
the benefit/risk of the combination for the Expansion Cohorts.
The Expansion Stage is evaluating the efficacy and safety of cabozantinib 40 mg
qd in combination with atezolizumab 1200 mg q3w across 20 tumor-specific
cohorts of the following tumor types: RCC, UC, CRPC, NSCLC, triple negative
breast cancer (TNBC), ovarian cancer (OC), endometrial cancer (EC),
hepatocellular cancer (HCC), gastric cancer/gastroesophageal junction
cancer/lower esophageal cancer (GC/GEJC/LEC), colorectal cancer (CRC), H&N
cancer, and differentiated thyroid cancer (DTC). In order to establish the
individual contributions of the components of the combination therapy, the
Expansion Stage also includes three exploratory single-agent cabozantinib
cohorts (UC, CRPC, and NSCLC) and one single-agent atezolizumab cohort (CRPC).
The Study Oversight Committee (SOC) will review the efficacy and safety of the
initially enrolled subjects (approximately 30 subjects in each cohort) and may
recommend enrollment extension for up to 10 cohorts in which encouraging
clinical activity has been demonstrated. The SOC can also recommend additional
enrollment at a higher dose of cabozantinib (60 mg qd orally) in combination
with 1200 mg atezolizumab q3w IV for tumor cohorts with modest clinical
activity at cabozantinib 40 mg in combination with atezolizumab. The
single-agent atezolizumab cohort will initially enroll 10 subjects. Enrollment
with approximately 30 subjects will depend on the observed efficacy among the
first 10 enrolled subjects. The Expansion Stage was initiated on 26 March 2018.
At the time of this protocol amendment the SOC has recommended extended
enrollment for Cohort 1 (clear cell RCC), Cohort 6 (CRPC), and Cohort 7 (NSCLC,
prior ICI therapy) following review of efficacy and safety data of the
initially enrolled subjects.
This amendment provides for subjects enrolling in the cohorts receiving
single-agent treatment with either cabozantinib or atezolizumab the opportunity
to receive combination treatment with cabozantinib and atezolizumab after
Investigator-assessed radiographic disease progression per Response Evaluation
Criteria in Solid Tumors (version 1.1) (RECIST 1.1) given these subjects meet
the eligibility criteria for receiving combination treatment (Second Agent
Add-On Stage).
Study objective
Dose-Escalation Stage (Combination Therapy Cohorts):
The primary objective is as follows:
• To determine the maximum tolerated dose (MTD) and/or recommended dose and
schedule for the subsequent Expansion Stage of daily oral administration of
cabozantinib in subjects with solid tumors when taken in combination with
atezolizumab.
The secondary objective is as follows:
• To evaluate the plasma pharmacokinetics (PK) of daily oral administration of
cabozantinib in subjects with solid tumors when given in combination with
atezolizumab.
• To assess safety of the combination therapy through the evaluation of
incidence and severity of nonserious adverse events (AEs) and serious adverse
events (SAEs), including immune-related adverse events (irAEs) and adverse
events of special interest (AESIs).
The exploratory objective is as follows:
• Correlation of immune cell, tumor cell, and blood biomarker analyses with
clinical outcome
• ORR as assessed by the Investigator per RECIST 1.1
Expansion Stage (Combination-Therapy Cohorts):
The primary objective and endpoint is as follows:
• To evaluate preliminary efficacy of the combination therapy by estimating the
ORR as assessed by the Investigator per RECIST 1.1
The secondary objective is as follows:
• To assess safety for the combination therapy through the evaluation of
incidence and severity of nonserious AEs and SAEs, including irAEs and AESIs.
The exploratory objectives and endpoints are as follows:
• ORR as assessed by the Investigator per immune-related RECIST (irRECIST) for
immune response
• Duration of response (DOR) as assessed by the Investigator per RECIST 1.1
• Progression-free survival (PFS) as assessed by the Investigator per RECIST 1.1
• ORR, DOR, and PFS as assessed by a Blinded Independent Radiology Committee
(BIRC) per RECIST 1.1 for selected cohorts
• Overall survival (OS)
• Correlation of immune cell, tumor cell, and blood biomarker analyses with
clinical outcome
• Changes in tumor infiltration and/or histology or other molecular changes as
determined from optional tumor biopsy
• To further evaluate the plasma pharmacokinetics (PK) of daily oral
administration of cabozantinib in subjects with solid tumors when given in
combination with atezolizumab.
• Tumor marker changes from baseline in select tumor indications
• Evaluation of mismatch repair (MMR) and microsatellite instability (MSI)
status in relevant tumor indications
• Changes in prostate-specific antigen (PSA response rate) from baseline for
CRPC cohorts
Exploratory Single-Agent Cabozantinib (SAC) Cohorts:
• Descriptive efficacy, safety, PK, and biomarker analyses of single-agent
cabozantinib (SAC) in UC, CRPC, and NSCLC subjects
• Descriptive efficacy and safety analyses of combination therapy after
progression on single-agent cabozantinib therapy
Exploratory Single-Agent Atezolizumab (SAA) Cohort:
• Descriptive efficacy, safety, PK, and biomarker analyses of single-agent
atezolizumab (SAA) in CRPC subjects
• Descriptive efficacy and safety analyses combination therapy after
progression on single-agent atezolizumab therapy
Study design
see enclosed protocol synopsis (study design)
Intervention
Please see ICF (Standard), Appendix 4: Study Procedures and Tests.
Study burden and risks
Please see protocol section 1.4: Overall Risk Benefit Assessment.
Harbor Bay Parkway 1851
Alameda CA 94502
US
Harbor Bay Parkway 1851
Alameda CA 94502
US
Listed location countries
Age
Inclusion criteria
see protocol (enclosed to submission)
Exclusion criteria
see protocol (enclosed to submission)
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-001792-24-NL |
| CCMO | NL62108.091.17 |