Trial Title:
Vismodegib Combined With Atezolizumab in Platinum Resistant Ovarian, Fallopian Tube, and Primary Peritoneal Cancer
NCT ID:
NCT05538091
Condition:
Platinum-Resistant Fallopian Tube Carcinoma
Platinum-Resistant Primary Peritoneal Carcinoma
PARP Inhibitor
Hedgehog Inhibitor
Conditions: Official terms:
Carcinoma
Atezolizumab
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Vismodegib
Description:
A small-molecule SMO inhibitor designed to specifically target the hedgehog pathway, a
known driver of BCC. It systemically inhibits hedgehog pathway signaling. Following
mutation, SMO is released from the inhibitory effect of PTCH and moves to the cell
surface, activating GLI. GLI travels to the nucleus and initiates transcription of target
genes that regulate basal cell growth and proliferation.
Arm group label:
vismodegib + atezolizumab
Other name:
ERIVEDGE
Intervention type:
Drug
Intervention name:
Atezolizumab
Description:
Atezolizumab is a humanized monoclonal antibody immune checkpoint inhibitor that
selectively binds to PD-L1 to stop the interaction between PD-1 and B7.1 (CD80
receptors). The antibody still allows interaction between PD-L2 and PD-1.
Arm group label:
vismodegib + atezolizumab
Other name:
Tecentriq
Summary:
This trial will treat patients with platinum resistant ovarian, fallopian tube or primary
peritoneal cancer as defined by a progression free interval within six months of
completion of most recent platinum-based treatment with a combination of vismodegib and
atezolizumab. Despite recent improvements in treatment of ovarian cancer with the
introduction of PARP inhibitors, response rates to therapy in the platinum resistant
setting remain dismal with response rates of only 10-20% reported for single agent
cytotoxic therapies. Given the poor prognosis and limited treatment options for these
patients, this population is considered appropriate for trials of novel therapeutic
candidates.
Detailed description:
While 5-year survival rates for early stage disease are approximately 90%, survival drops
to 30% in advanced stage disease. Symptoms preceding diagnosis are often non-specific and
vague. Moreover, there is no effective screening test. As a result, over 75% of patients
are diagnosed with advanced stage disease, which leads to the high mortality rate.
Regardless of BRCA mutation status, patients who develop recurrent disease will all
ultimately progress to develop therapy resistant disease and ultimately die. The use of
PARP inhibitor maintenance therapy after either a complete or partial response to
frontline platinum based therapy has demonstrated a more dramatic improvement in
progression free survival, with the largest benefit noted in those patients with a BRCA
mutation, followed by those whose tumors are noted to be homologous recombination
deficient and lastly a modest benefit for those cancers that are BRCA wild-type and
homologous recombination proficient. This trial will employ the combination of vismodegib
and atezolizumab as it has been shown that inhibition of hedgehog signaling in the tumor
stroma can reverse tumor desmoplasia. The benefit-risk ratio for atezolizumab in
combination with vismodegib is expected to be acceptable in this setting.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Signed Informed Consent Form
- Age ≥ 18 years at time of signing Informed Consent Form
- Ability to comply with the study protocol, in the investigator's judgment
- Histologically or cytologically confirmed epithelial ovarian, fallopian tube or
primary peritoneal cancer
- Platinum resistant disease, defined by disease progression during or following
treatment with platinum-based chemotherapy within 6 months of completing therapy
- Measurable or non-measurable but evaluable disease per RECIST v1.1 {Previously
irradiated lesions can be considered as measurable disease only if progressive
disease has been unequivocally documented at that site since radiation.}
- Availability of a representative tumor specimen for exploratory biomarker research
will be required for 12 patients (see Section 5.4.5 for information on tumor
specimens)
- ECOG Performance Status of 0-1
- Life expectancy ≥ 3 months
- Adequate hematologic and end-organ function, defined by the following laboratory
test results, obtained within 14 days prior to initiation of study treatment: ANC ≥
1.5 ⋅ 109/L (1500/μL) without granulocyte colony-stimulating factor support;
Lymphocyte count ≥ 0.5 ⋅ 109/L (500/μL); Platelet count ≥ 100 ⋅ 109/L (100,000/μL)
without transfusion; Hemoglobin ≥ 80 g/L (8 g/dL) (Patients may be transfused to
meet this criterion.)
- AST, ALT, and alkaline phosphatase (ALP) ≤ 2.5 ⋅ upper limit of normal (ULN),
with the following exceptions:
- Patients with documented liver metastases: AST and ALT ≤ 5 ⋅ ULN
- Patients with documented liver or bone metastases: ALP ≤ 5 ⋅ ULN
- Serum bilirubin ≤ 1.5 ⋅ ULN with the following exception:
- Patients with known Gilbert disease: serum bilirubin ≤ 3 ⋅ ULN
- Serum creatinine ≤ 1.5 ⋅ ULN
- Serum albumin ≥ 25 g/L (2.5 g/dL)
- For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 1.5 ⋅ ULN
- For patients receiving therapeutic anticoagulation: stable anticoagulant
regimen
- Negative HIV test at screening, with the following exception: patients with a
positive HIV test at screening are eligible if they are stable on anti-retroviral
therapy, have a CD4 count > 200, and have an undetectable viral load.
- Negative hepatitis B surface antigen (HBsAg) test at screening
- For women of childbearing potential: agreement to remain abstinent (refrain from
heterosexual intercourse) or use contraceptive methods as defined below:
- Women must remain abstinent or use contraceptive methods with a failure rate of
< 1% per year during the treatment period and for 5 months after the final dose
of atezolizumab and for 24 months after the final dose of vismodegib. Women
must refrain from donating eggs during this same period.
- A woman is considered to be of childbearing potential if she is postmenarchal,
has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea
with no identified cause other than menopause), and has not undergone surgical
sterilization (removal of ovaries and/or uterus). The definition of
childbearing potential may be adapted for alignment with local guidelines or
requirements.
- Examples of contraceptive methods with a failure rate of < 1% per year include
bilateral tubal ligation, male sterilization, hormonal contraceptives that
inhibit ovulation, hormone-releasing intrauterine devices, and copper
intrauterine devices.
- The reliability of sexual abstinence should be evaluated in relation to the
duration of the clinical trial and the preferred and usual lifestyle of the
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or
postovulation methods) and withdrawal are not adequate methods of
contraception.
Exclusion Criteria:
- Inability or unwillingness to swallow capsules
- Inability or unwillingness to comply with study procedures
- History of leptomeningeal disease
- Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
drainage procedures (once monthly or more frequently)
o 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, 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 (see Appendix 9) for a more comprehensive list of
autoimmune diseases and immune deficiencies), with the following exceptions:
- Patients with a history of autoimmune-related hypothyroidism who are on
thyroid-replacement hormone are eligible for the study.
- Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen
are eligible for the study.
- Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis are
excluded) are eligible for the study provided all of following conditions are
met:
- Rash must cover < 10% of body surface area
- Disease is well controlled at baseline and requires only low-potency topical
corticosteroids
- No occurrence of acute exacerbations of the underlying condition requiring psoralen
plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral
calcineurin inhibitors, or high-potency or oral corticosteroids within the previous
12 months
- History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of
active pneumonitis on screening chest computed tomography (CT) scan (History of
radiation pneumonitis in the radiation field (fibrosis) is permitted).
- Active tuberculosis
- Significant cardiovascular disease (such as New York Heart Association Class II or
greater cardiac disease, myocardial infarction, or cerebrovascular accident) within
3 months prior to initiation of study treatment, unstable arrhythmia, or unstable
angina
- Major surgical procedure, other than for diagnosis, within 4 weeks prior to
initiation of study treatment, or anticipation of need for a major surgical
procedure during the study
- History of malignancy other than ovarian cancer within 5 years prior to screening,
with the exception of malignancies with a negligible risk of metastasis or death
(e.g., 5-year OS rate > 90%), such as adequately treated carcinoma in situ of the
cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in
situ, or Stage I uterine cancer
- 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 allogeneic stem cell or solid organ transplantation
- Any other disease, metabolic dysfunction, physical examination finding, or clinical
laboratory finding that contraindicates the use of an investigational drug, may
affect the interpretation of the results, or may render the patient at high risk
from treatment complications
- Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of
study treatment, or anticipation of need for such a vaccine during atezolizumab
treatment or within 5 months after the final dose of atezolizumab
- Current treatment with anti-viral therapy for HBV
- Treatment with investigational therapy within 28 days prior to initiation of study
treatment
- 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
- Treatment with systemic immunosuppressive medication (including, but not limited to,
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and
anti-TNF-α agents) within 2 weeks prior to initiation of study treatment, or
anticipation of need for systemic immunosuppressive medication during study
treatment, with the following exceptions:
- Patients who received acute, low-dose systemic immunosuppressant medication or
a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours
of corticosteroids for a contrast allergy) are eligible for the study after
Principal Investigator confirmation has been obtained.
- Patients who received mineralocorticoids (e.g., fludrocortisone),
corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or
low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency
are eligible for the study.
- History of severe allergic anaphylactic reactions to chimeric or humanized
antibodies or fusion proteins
- Known hypersensitivity to Chinese hamster ovary cell products or to any component of
the atezolizumab formulation
- Known allergy or hypersensitivity to any component of the vismodegib formulation
- Agreement not to donate blood or blood products during the study and for 24 months
after discontinuation of vismodegib.
- Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment
or within 5 months after the final dose of atezolizumab and for 24 months after the
final dose of vismodegib.
- Women of childbearing potential must have a negative serum pregnancy test
result within 14 days prior to initiation of study treatment.
Gender:
Female
Gender based:
Yes
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
UPMC Hillman Cancer Center
Address:
City:
Pittsburgh
Zip:
15232
Country:
United States
Status:
Recruiting
Contact:
Last name:
Joshua J Plassmeyer, MS
Phone:
412-648-6417
Email:
plassmeyerjm@upmc.edu
Investigator:
Last name:
Ronald Buckanovich, MD
Email:
Principal Investigator
Start date:
May 15, 2023
Completion date:
April 1, 2028
Lead sponsor:
Agency:
Ronald Buckanovich
Agency class:
Other
Collaborator:
Agency:
Genentech, Inc.
Agency class:
Industry
Source:
University of Pittsburgh
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05538091
