Combination Immunotherapy in Biochemically Recurrent Prostate Cancer

Study Overview
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Brief Summary
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Background: Some people with prostate cancer have a rise in prostate-specific antigen (PSA). This can happen even after treatments like radiation and surgery. Androgen deprivation therapy (ADT) drugs and close monitoring are one standard way to treat this group of people. Another way is to monitor people and their PSA values over time. Researchers want to see if a combination of new drugs can help these people. Objective: To see if the combination treatment of PROSTVAC, CV301, and MSB0011359C (M7824) can induce an anti-tumor attack in people with biochemically recurrent prostate cancer. Eligibility: People ages 18 and older with certain kinds of prostate cancer Design: Participants will be screened with Medical history Physical exam Blood and urine tests A scan of the neck, chest, abdomen, and pelvis A bone scan A sample of tissue that was already taken will be tested. This will confirm the diagnosis, stage, and disease status. Some participants will have close monitoring with four monthly PSA checks. All participants will get two study drugs as shots under the skin. They will get the third drug in a vein. They will get the drugs over at least 7 months. Their vital signs will be checked before they get the drugs and for up to 1 hour after. Participants will have frequent study visits. They will have physical exams, urine and blood tests, and scans. Participants will return to the clinic about 4 weeks after they stop taking the study drugs. They will have a medical history, physical exam, and blood tests. They may also have long-term follow-up visits.

Detailed Description
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Background: Androgen deprivation therapy (ADT) and surveillance are treatment options for prostate cancer patients with biochemical progression after localized therapy (i.e., biochemically recurrent [BCR] prostate cancer). The primary goal in these patients is to prevent morbidity from their cancer that results from disease progression and metastatic disease on conventional imaging. ADT can lower the PSA in these patients, but because of its substantial side effect profile and ambiguous long-term impact, it is generally deferred by most patients until there is a rapid escalation in their PSA. Immunotherapy presents an alternative option for these patients that is especially attractive because it is not associated with substantial toxicity. Also, since immunotherapy can have lasting effects after treatment due to a sustained activated immune response, patients will not be required to take these treatments indefinitely to potentially benefit clinically. Current and previous clinical trials have demonstrated that single agent immunotherapy can impact PSA in patients in this population. The focus of this study is to determine if combination immunotherapy with immune-cell mobilizing vaccines can initiate an immune response in the first 4 months that is then augmented by an immune checkpoint inhibitor in the following 3 months. In addition to PSA responses (the primary metric in this population), safety, changes in immune responses, and PSA kinetics will also be evaluated. Objectives: Primary Objectives: Safety Lead-In: To evaluate the safety and tolerability of combination immunotherapy in participants with castration-resistant prostate cancer Biochemical Recurrence: To determine if the combination immunotherapy can induce a 30% decline in PSA in 28% of participants with biochemically recurrent prostate cancer. Eligibility Criteria (for biochemical recurrence): Histologically confirmed adenocarcinoma of the prostate Participants with negative CT Scan and Tc-99m Bone Scan Participants with a PSA over 0.8 ng/ml for participants following radical prostatectomy or for participants following definitive radiation therapy: a rise in PSA of >= 2 ng/mL above the nadir Participants with a PSA doubling time of 5-15 months No history of active autoimmune disease or history of organ compromising autoimmune disease ECOG 0-1 Safety lead-in cohort will evaluate 6 participants with castration resistant prostate cancer Design: Three-arm, non-randomized study Accrual goal is a total of 37 evaluable participants (6 in an initial safety cohort, 6 participants who received M7824 as part of the initial investigation and 25 homogenously treated participants) to evaluate response Participants from an on-going study (NCT02649439) with nearly identical eligibility can serve as a contemporary control for secondary endpoints Following the safety lead-in, all participants will be enrolled and may undergo a surveillance period during which up to 4 consecutive monthly PSA values will be captured by the labs. After surveillance period, if applicable, participants will be treated with 2 vaccines concurrently, Prostvac and CV301, during months 1-4. For months 5-7, MSB0011359C [an anti-PD-L1 antibody (avelumab) with TGF(Beta)-Trap molecule] will be added to the regimen. -Effective with amendment v7/29/2021, MSB0011359C will no longer be given as part of the treatment combination for the Biochemical Recurrence cohort (Arms 2 and 3) Participants will be monitored for on-treatment and post-treatment PSA, immune and imaging responses.

Official Title
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Phase II Trial of Combination Immunotherapy in Biochemically Recurrent Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Biological: PROSTVAC-V
* Biological: PROSTVAC-F
* Drug: MSB0011359C (M7824)
* Biological: CV301


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Histopathological documentation of prostate cancer confirmed in either the Laboratory of Pathology at the National Institutes of Health (NIH) Clinical Center, or Walter Reed National Military Medical Center prior to enrollment. If no pathologic specimen is available, participants may enroll with a pathologist s report showing a histologic diagnosis of prostate cancer and a clinical course consistent with the disease. Recovery to baseline from acute toxicity related to prior therapy, including surgery and radiation. (28 days removed from last systemic therapy, 14 days removed from last radiation therapy). Hepatic function eligibility parameters (within 16 days before starting therapy): --Bilirubin less than or equal to ULN (OR in participants with Gilbert s syndrome, a total bilirubin less than or equal to 3.0), AST and ALT less than or equal to 1.5 times upper limit of normal. Adequate renal function defined by an estimated creatinine clearance > 50 mL/min according to the Cockcroft-Gault formula or by measure of creatinine clearance from 24 hour urine collection. No other active malignancies within the past 36 months (with the exception of nonmelanoma skin cancers or carcinoma in situ of the bladder) or life-threatening illnesses. Willing to travel to the NIH for follow-up visits. 18 years of age or older. Able to understand and sign informed consent. The effects Prostvac and CV301 on the developing human fetus are unknown. For this reason, men must agree to use highly effective contraception (that is, methods with a failure rate of less than 1% per year) prior to study entry, for the duration of study therapy and at least four months after the last treatment administration. Should a woman become pregnant or suspect she is pregnant while her partner is participating in this study, she should inform her treating physician immediately. Additional Inclusion Criteria Specific to Safety Lead-In Cohort Castrate testosterone level (<50ng/dl or 1.7nmol /L) Progressive disease at study entry defined as one or more of the following criteria occurring in the setting of castrate levels of testosterone: Radiographic progression defined as any new or enlarging bone lesions or growing lymph node disease, consistent with prostate cancer OR PSA progression defined by sequence of rising values separated by >1 week (2 separate increasing values over a minimum of 2ng/ml (PCWG2 PSA eligibility criteria). If participants had been on flutamide, PSA progression is documented 4 weeks or more after withdrawal. For participants on bicalutamide or nilutamide disease progression is documented 6 or more weeks after withdrawal. --Participants must agree to continuation of androgen deprivation therapy (ADT) with a gonadotropin-releasing hormone agonist/antagonist or bilateral orchiectomy ECOG performance status of 0-2 (Karnofsky >80%). Hematological eligibility parameters (within 16 days before starting therapy): Granulocyte count greater than or equal to 1000/mm^3 Platelet count greater than or equal to 100 000/mm^3 Hgb greater than or equal to 9 g/dL PT less than or equal to 1.5 x ULN aPTT less than or equal to 1.5 x ULN Additional Inclusion Criteria Specific to Biochemical Recurrence Cohort Biochemical progression defined as follows: For participants following definitive radiation therapy: a rise in PSA of greater than or equal to 2 ng/mL above the nadir (per RTOG-ASTRO consensus criteria) For participants following radical prostatectomy: rising PSA after surgical procedure (participants must have a PSA greater than or equal to 0.8 ng/mL) Participants must have a rising PSA as confirmed by 3 values a minimum of 1 week apart over at least a 1 month period of time. Participants must have a PSA doubling time of 5-15 months. ECOG performance status of 0-1 (Karnofsky greater than or equal to 80%). Negative CT scan/MRI and bone scan for metastatic prostate cancer. Baseline testosterone greater than or equal to 100 ng/dl. PSA less than or equal to 30 ng/mL. Hematological eligibility parameters (within 16 days before starting therapy): Granulocyte count greater than or equal to 1000/mm3 Platelet count greater than or equal to 100 000/mm3 Hgb greater than or equal to 10 g/dL EXCLUSION CRITERIA: Immunocompromised status due to: Human immunodeficiency virus (HIV) positivity. Active autoimmune diseases such as Addison's disease, Hashimoto's thyroiditis, systemic lupus erythematosus, Sjogren syndrome, scleroderma, myasthenia gravis, Goodpasture syndrome or active Grave's disease. Participants with a history of autoimmunity that has not required systemic immunosuppressive therapy or does not threaten vital organ function including CNS, heart, lungs, kidneys, skin, and GI tract will be allowed. Participants with diabetes type I, vitiligo, or alopecia are allowed. Other immunodeficiency diseases Splenectomy Receipt of any organ transplantation, including allogeneic stem-cell transplantation, but with the exception of transplants that do not require immunosuppression (e.g. corneal transplant, hair transplant). Chronic administration (defined as daily or every other day for continued use > 14 days) of systemic corticosteroids within 28 days before the first planned dose of investigational therapy. Use of corticosteroids with minimal systemic absorption (e.g. inhaled steroids, nasal sprays, and topical agents) is allowed. Serious intercurrent medical illness that, in the judgment of the investigator, would interfere with participant s ability to carry out the treatment program. Other medications used for urinary symptoms including 5-alpha reductase inhibitors (finasteride and dutasteride) and alternative medications known to alter PSA (e.g. phytoestrogens and saw palmetto). History of prior chemotherapy (chemotherapy allowed for lead-in cohort in castration resistant disease.) History of prior immunotherapy within the last 3 years (immunotherapy allowed for lead-in cohort in castration resistant disease.) Receipt of an investigational agent within 28 days (or 56 days for an antibody-based therapy) before the first planned dose of study drugs. Major surgery within 4 weeks prior to enrollment History of allergic reactions attributed to compounds of similar chemical or biologic composition to poxviral vaccines (e.g., vaccinia vaccine) Previous serious adverse reactions to smallpox vaccination History of allergic reactions attributed to monoclonal antibodies (grade 3) Known allergy to eggs, egg products, aminoglycoside antibiotics (e.g. gentamicin or tobramycin). History of atopic dermatitis or active skin condition (acute, chronic, exfoliative) that disrupts the epidermis Unable to avoid close contact or household contact with the following high-risk individuals for three weeks after the Day 1 vaccination: (a) children less than or equal to 3 years of age, (b) pregnant or nursing women, (c) individuals with prior or concurrent extensive eczema or other eczemoid skin disorders, or (d) immunocompromised individuals, such as those with HIV. Participants who test positive for HBV or HCV Clinically significant cardiovascular/cerebrovascular disease as follows: cerebral vascular accident/stroke (< 6 months prior to the first planned dose of study drugs), myocardial infarction (< 6 months prior to the first planned dose of study drugs), unstable angina, congestive heart failure (New York Heart Association Classification Class greater than or equal to II), serious cardiac arrhythmia, or uncontrolled hypertension (SBP>170/DBP>105). Participants who have received a red cell transfusion within 2 weeks prior to enrollment. Participants unwilling to accept blood products as medically indicated. Individual tumor lesion(s) in the liver or chest which are 10 cm or larger.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1/combination therapy (closed December 2018)<br>Prostvac + CV301+ MSB0011359C | Biological: PROSTVAC-V<br>* Recombinant vaccinia virus vector vaccine of the genus Orthopoxvirus. Administered by subcutaneous injection.<br>Biological: PROSTVAC-F<br>* Recombinant fowlpox virus vector vaccine of the genus Avipoxvirus. Administered by subcutaneous injection.<br>Drug: MSB0011359C (M7824)<br>* Fully human bifunctional fusion protein that combines IgG1 anti-PD-L1 and TGFbetaRII as a monoclonal antibody. Administered via IV infusion over 1 hour.<br>Biological: CV301<br>* Recombinant vaccinia virus vaccine of the genus Avipoxvirus. Administered subcutaneously.<br>|
| Experimental: 2/combination therapy + surveillance (closed)<br>Surveillance followed by Prostvac + CV301 then Prostvac + CV301 + MSB0011359C | Biological: PROSTVAC-V<br>* Recombinant vaccinia virus vector vaccine of the genus Orthopoxvirus. Administered by subcutaneous injection.<br>Biological: PROSTVAC-F<br>* Recombinant fowlpox virus vector vaccine of the genus Avipoxvirus. Administered by subcutaneous injection.<br>Drug: MSB0011359C (M7824)<br>* Fully human bifunctional fusion protein that combines IgG1 anti-PD-L1 and TGFbetaRII as a monoclonal antibody. Administered via IV infusion over 1 hour.<br>Biological: CV301<br>* Recombinant vaccinia virus vaccine of the genus Avipoxvirus. Administered subcutaneously.<br>|
| Experimental: 3/combination vaccine therapy +/- surveillance<br>Surveillance as needed followed by Prostvac + CV301 | Biological: PROSTVAC-V<br>* Recombinant vaccinia virus vector vaccine of the genus Orthopoxvirus. Administered by subcutaneous injection.<br>Biological: PROSTVAC-F<br>* Recombinant fowlpox virus vector vaccine of the genus Avipoxvirus. Administered by subcutaneous injection.<br>Biological: CV301<br>* Recombinant vaccinia virus vaccine of the genus Avipoxvirus. Administered subcutaneously.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| deterimine if combination immunotherapy can result in 30% decline in PSA | fraction of evaluable subjects who experience at least a 30% decline from the maximum to the minimum PSA value while on study | 6 months, one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| slope of the PSA change over time | The slopes obtained after administering the vaccines alone or in combination with the checkpoint inhibitor will be tested vs the slopes obtained prior to administering the vaccines, using a two-tailed 0.05 significance level paired t-test or Wilcoxon signed rank test (if the paired differences are not normally distributed) | end of treatment | 
| fraction of subjects with grade 3 and grade 4 adverse events | Reprting the grade of adverse events noted in each participant and reporting the fraction with grade 3 and grade 4 adverse events | 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vaccine, PSA, Immunotherapy, Immune Response, Checkpoint Inhibitor