CASPAR - A Phase III Trial of Enzalutamide and Rucaparib as a Novel Therapy in First-line Metastatic Castration-Resistant Prostate Cancer
To compare radiographic progression-free survival (rPFS) and overall survival (OS) with enzalutamide and rucaparib versus enzalutamide alone for patients with metastatic castration resistant prostate cancer commencing first-line therapy.
In patients commencing enzalutamide as the first-line therapy for metastatic castration resistant prostate cancer, to evaluate the effects of concurrent administration of rucaparib on:
- rPFS and OS within HRR mutant and wild-type patients
- Time to unequivocal clinical progression
- Best radiographic response using prostate cancer working group 3 (PCWG3) criteria
- Duration of overall response
- PSA response rate
- Best response by serum PSA by months 7 and 13 using categorical and continuous measures.
- Time to first symptomatic skeletal event (SSE)
- Safety and tolerability as measured by NCI Common Toxicity Criteria; trial discontinuation for treatment emergent toxicities
- Histologic/cytologic documentation of prostate adenocarcinoma
- Adequate archival tumor specimen or archival slides
- Progressive disease must be demonstrated at study entry while the patient is on continuous androgen deprivation therapy (ADT) or status post orchiectomy
- Measurable or non-measurable metastatic disease
- No prior therapy for metastatic castration-resistant prostate cancer
- >= 2 weeks or 5 half-lives (whichever is shorter) since prior therapy
- No prior therapy with enzalutamide, rucaparib or any other PARP inhibitor, or platinum chemotherapy
- Prior docetaxel and/or novel anti-androgen use is allowed only if given in the hormone-sensitive non-metastatic or metastatic, or castration-resistant non-metastatic disease setting
- Patient must have discontinued all previous treatments for cancer (except ADT and bone anti-responsive therapies such as denosumab or zoledronic acid)
- Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- Normal lab values
- No clinically suspected central nervous system (CNS) (leptomeningeal or parenchymal) metastases
- No known or suspected history of cytopenia
- No blood product transfusion, granulocyte/granulocyte-macrophage-colony stimulating factor (G-CSF/GM-CSF), or erythropoietin/thrombopoietin use within 14 days of pre-registration
- No significant cardiac history
- No history of seizure or any condition that may increase the patient's seizure risk within 2 years
- Other inclusion/exclusion criteria are present. Please contact the study team for a complete list.
Phase III Randomized Trial of Standard Systemic Therapy (SST) Versus Standard Systemic Therapy Plus Definitive Treatment (Surgery or Radiation) of the Primary Tumor in Metastatic Prostate Cancer)
To compare overall survival in metastatic prostate cancer patients who are randomized to standard systemic therapy (SST) plus definitive treatment of the primary tumor versus standard systemic therapy alone.
- To compare overall survival in metastatic prostate cancer patients who received SST plus surgical excision of the primary tumor versus SST alone in the subset who specify the surgical intent stratification factor.
- To compare the rate of symptomatic local progression between the treatment arms.
- To compare progression-free survival (PFS) between the two treatment arms.
- To compare rates of progression-free survival between arms for the subsets of patients with and without metastasis directed therapy (MDT) to oligometastatic sites.
- All patients must have a histologically or cytologically proven diagnosis of adenocarcinoma of the prostate. Patients with pure small cell carcinoma* (SCC), sarcomatoid, or squamous cell carcinoma are not eligible. (*morphology must be consistent with SCC; synaptophysin or chromogranin positive by immunohistochemical staining is insufficient to diagnose SCC).
- Patients must have an intact prostate. No prior local therapy for prostate adenocarcinoma is allowed (e.g., brachytherapy, high-intensity focused ultrasound [HIFU], cryotherapy, laser ablative therapies). Any prior therapy for benign conditions, such as obstruction, are acceptable (e.g., transurethral resection of the prostate, greenlight laser ablation, microwave ablation).
- Patients must have evidence of metastatic disease on technetium bone scan and computed tomography (CT) or magnetic resonance imaging (MRI) within 42 days prior to starting standard systemic therapy. Metastatic disease that is detected by positron emission tomography (PET) scan only (sodium fluoride [NaF], prostate-specific membrane antigen [PSMA], anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid [FACBC], carbon [C]11) but not conventional imaging (technetium [Tc]99 bone scan, CT or MRI) or solitary metastases by conventional imaging, must be confirmed histologically or cytologically.
- Patients with known brain metastases are not eligible. Brain imaging studies are not required for eligibility if the patient has no neurologic signs or symptoms suggestive of brain metastasis. If brain imaging studies are performed, they must be negative for disease.
- Patients must have received no more than 28 weeks of standard systemic therapy (SST). SST is defined as current National Comprehensive Cancer Network (NCCN) guidelines for metastatic prostate cancer.
- Patients must not have progressed while on SST.
- Patients with oligometastatic prostate cancer may receive metastasis directed therapy to up to four sites of disease prior to randomization.
- Patients must have a complete physical examination and medical history within 28 days prior to registration.
- Patients must have a PSA documented prior to initiation of SST and within 28 days prior to registration. Any additional PSAs measured while receiving SST should be recorded.
- Patients must have a testosterone lab documented within 28 days prior to randomization. Any additional testosterone labs measured while receiving SST should be recorded as well as pretreatment initiation if available.
- No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, adequately treated stage 0, I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years.
- Patients must be offered the opportunity to participate in translational medicine studies and specimen banking for future studies.
- Patients who can complete Patient-Reported Outcome instruments in English, Spanish or French, must participate in the quality of life studies.
- Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines.
Immunotherapy With Nivolumab and Ipilimumab Followed by Nivolumab or Nivolumab With Cabozantinib for Patients With Advanced Kidney Cancer, The PDIGREE Study
To compare the overall survival (OS) in patients with metastatic RCC treated with ipilimumabnivolumab followed by either nivolumab versus cabozantinib-nivolumab.
- To determine PFS of patients treated with nivolumab versus nivolumab-cabozantinib
- To evaluate the 12-month complete response rate in patients treated with ipilimumabnivolumab followed by cabozantinib-nivolumab versus ipilimumab-nivolumab followed by nivolumab (patients who have CR and relapse before 12 months will not be counted as a CR at 12-months)
- To evaluate the rates of discontinuing therapy at 1 year
- To compare objective response rates (ORR, assessed by RECIST 1.1 and irRECIST criteria) for patients treated with ipilimumab-nivolumab followed by cabozantinib-nivolumab versus ipilimumab-nivolumab followed by nivolumab.
- To document the adverse event profile of ipilimumab-nivolumab followed by cabozantinibnivolumab.
- Histologically documented renal cell carcinoma with clear cell component, including patients who have sarcomatoid features.
- Any metastatic disease, including visceral, lymph node, other soft tissue and bone, measurable per RECIST 1.1.
- Measurable disease as defined in the protocol.
- Must be intermediate or poor risk patient per International Metastatic Renal Cell Carcinoma Database (IMDC) criteria (1 or more of the following: Karnofsky performance status [KPS] < 80, < 1 year from diagnosis [including initial nephrectomy] to systemic treatment for metastatic disease, hemoglobin less than lower limit of normal [LLN], corrected calcium concentration greater than upper limit of normal [ULN], absolute neutrophil count greater than ULN, platelet count > ULN).
- Central nervous system (CNS) disease permitted, if stable and not otherwise causing symptoms or needing active treatment.
- Karnofsky performance status >= 70%.
- No prior treatment with PD-1, PD-L1, or CTLA-4 targeting agents (including but not limited to nivolumab, pembrolizumab, pidilizumab, durvalumab, atezolizumab, tremelimumab, and ipilimumab), or any other drug or antibody specifically targeting T-cell co-stimulation or checkpoint pathways. The only exception is for prior treatment with nivolumab or other PD-1/PD-L1/CTLA-4 targeting therapy on pre- or post-operative trials, as long as > 1 year since completion of systemic therapy.
- No prior previous systemic therapy for renal cell carcinoma (prior HD IL-2 [> 28 days] and prior adjuvant sunitinib > 180 days since completion and prior immunotherapy as above are allowed).
- No cancer therapy less than 28 days prior to registration; this includes radiation therapy, except for bone lesions less than 14 days prior to registration. There must be a complete recovery and no ongoing complications from radiotherapy.
- Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing potential only, a negative serum or urine pregnancy test done =< 14 days prior to registration is required.
- Age >= 18 years
- Absolute neutrophil count (ANC) >= 1,500/mm^3.
- Platelet count >= 100,000/mm^3.
- Hemoglobin >= 8 g/dL.
- Calculated (Calc.) creatinine clearance >= 30 mL/min.
- Urine protein =< 1+ or urine protein to creatinine (UPC) ratio < 1.
- Total bilirubin =< 1.5 x upper limit of normal (ULN).
- Aspartate aminotransferase/alanine aminotransferase (AST/ALT) =< 2.5 x upper limit of normal (ULN) or < 5 x ULN if hepatic metastases present.
- STEP 2 REGISTRATION ELIGIBILITY CRITERIA
- Successful completion of at least 1 cycle of ipilimumab/nivolumab.
- Resolution of any treatment-related adverse events to grade 1 or less per dose modification section (this criteria does not include any adverse events [AEs] not attributable to treatment which are present due to disease). Exceptions for this criteria include patients receiving replacement hormone treatments (such as levothyroxine for treatment-related hypothyroidism or glucocorticoid replacement for adrenal insufficiency). Please contact study chair if further discussion is needed.
- No more than 70 days from last dose of ipilimumab/nivolumab.
Phase III Randomized Adjuvant Study of MK-3475 (Pembrolizumab) in Muscle Invasive and Locally Advanced Urothelial Carcinoma (Ambassador) versus Observation
To determine DFS and OS in all patients with muscle-invasive bladder and upper-tract urothelial carcinoma treated with adjuvant MK-3475 (pembrolizumab) vs. observation.
- To determine DFS and OS in PD-L1 positive and negative patients with muscle-invasive bladder and upper-tract urothelial carcinoma treated with adjuvant MK-3475 (pembrolizumab) vs. observation.
- To characterize the safety and tolerability of MK-3475 (pembrolizumab) when administered in the adjuvant setting in patients with muscle-invasive bladder and upper-tract urothelial carcinoma.
Results of the primary analysis will be examined for consistency, while taking into account the stratification factors and/or covariates of baseline QOL and fatigue.
- Histologically confirmed muscle-invasive urothelial carcinoma of the bladder, urethra, upper tract, or lymph node positive (LN+) disease; variant histology allowed as long as urothelial carcinoma is predominant (any amount of squamous differentiation is allowed); any component of neuroendocrine carcinoma is excluded
- Paraffin tissue samples obtained by transurethral resection of muscle-invasive bladder tumor, upper tract resection, or other surgery must be available; this specimen submission is mandatory prior to registration as results will be used for stratification; specimens from radical/definitive surgery (radical cystectomy/nephrectomy/ureterectomy /nephroureterectomy/cystoprostatectomy and LN dissection) are preferred over transuretheral resection, if available
- Patient must fit into one of the following three categories:
- Patients who received neoadjuvant chemotherapy and pathologic stage at surgical resection is >= pT2 and/or N+ OR
- Patients who are not cisplatin-eligible (according to >= 1 of the following criteria: Eastern Cooperative Oncology Group [ECOG] performance status of 2, creatinine clearance <60 mL/min, grade >= 2 hearing loss, grade >= 2 neuropathy, or New York Heart Association class III heart failure and pathologic stage at surgical resection is >= pT3 or pN+) OR
- Patients that decline adjuvant cisplatin-based or other systemic chemotherapy based on an informed discussion with the physician and pathologic stage at surgical resection is >= pT3 or pN+
- The 7th edition of American Joint Committee on Cancer staging will be utilized; patient must have had radical cystectomy (cystoprostatectomy for men) and lymph node dissection (for bladder primary), or nephrectomy, nephroureterectomy or ureterectomy (for uppertract tumors) or urethrectomy (in addition to a radical cystectomy-either simultaneously or in the past) >= 4 weeks but =< 16 weeks prior to pre-registration; patients who have had a partial cystectomy as definitive therapy are not eligible
- No gross cancer at the surgical margins; microscopic invasive urothelial carcinoma positive margins are allowed; carcinoma in situ (CIS) at margins is considered negative margins
- No evidence of residual cancer or metastasis after surgery; patients with upper tract urothelial carcinoma must have a negative cystoscopy within 3 months prior to pre-registration; if the bladder has been removed a cystoscopy is not required
- No metastatic disease (or radiologic findings "concerning" for metastatic disease) on cross-sectional imaging (according to Response Evaluation Criteria in Solid Tumors [RECIST] version [v]1.1 criteria)
- No active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids; these include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome because of the risk of recurrence or exacerbation of disease; human immunodeficiency virus (HIV) (+) patients are eligible as long as they have: cd4 > 200, undetectable viral load and on highly active antiretroviral therapy (HAART) therapy
- No current pneumonitis or prior history of non-infectious pneumonitis that required steroids within the previous 5 years
- Patients with vitiligo, endocrine deficiencies including type I diabetes mellitus, thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible