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.
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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
48
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.
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.
UPMC Hillman Cancer Center
Pittsburgh, Pennsylvania, United States
RECRUITINGSafety Determined by Dose Limiting Toxicities (DLTs)
Immune-related and other adverse events and/or serious adverse events related to treatment occurring within the first two cycles of treatment that require a dose reduction (Dose Limiting Toxicities (DLTs)). All adverse events will be tabulated by Type, Grade, Relatedness to Treatment and Expectedness, Cycle of Treatment, and by Dose Administered.
Time frame: Up to two weeks
Objective Response Rate (ORR)
Confirmed complete response or partial response by RECIST 1.1. Per RECIST v1.1. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: Up to 36 months
Immune-modified Response Rate by imRECIST
Confirmed complete response or partial response by imRECIST. Per imRECIST: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: Up to 36 months
Modified Response Rate by iRECIST
Confirmed complete response or partial response by iRECIST for immune-based therapeutics. Per iRECIST: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: Up to 36 months
Overall Survival (OS)
Time from trial enrollment until death from any cause.
Time frame: Up to 36 months
Progression-free survival (PFS)
Time from trial enrollment until disease progression by RECIST v1.1 or death from any cause. Progression as defined by RECIST v1.1 for target lesions: Progressive Disease (PD): smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). For non-target lesions: Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase
Time frame: Up to 36 months
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