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Nivolumab + Docetaxel + ADT in mHSPC Patients With DDRD or Inflamed Tumors

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04126070
Recruitment Status : Recruiting
First Posted : October 14, 2019
Last Update Posted : March 4, 2020
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Xiao X. Wei, Dana-Farber Cancer Institute

Brief Summary:

This research study is studying a combination of hormonal therapy, chemotherapy, and immunotherapy as a possible treatment for metastatic hormone-sensitive prostate cancer. The names of the study drugs involved in this study are:

  • Androgen deprivation therapy (ADT) with a drug of your physician's choice. This may include leuprolide (Lupron), goserelin acetate (Zoladex), or degarelix (Firmagon).
  • Docetaxel
  • Nivolumab

Condition or disease Intervention/treatment Phase
Hormone Sensitive Prostate Cancer Prostate Adenocarcinoma Metastasis Prostate Adenocarcinoma Drug: Androgen Deprivation Therapy Drug: Nivolumab Drug: Docetaxel Phase 2

Detailed Description:

This research study is a Phase 2 clinical trial. Phase 2 clinical trials test the safety and effectiveness of investigational drug(s) to learn whether the drug(s) work in treating a specific disease. "Investigational" means that the drug(s) are being studied.

The U.S. Food and Drug Administration (FDA) has not approved nivolumab for hormone sensitive prostate cancer. However, nivolumab has been approved for other uses, including for advanced melanoma, lung cancer, head and neck cancer, kidney cancer, and bladder cancer.

The U.S. FDA has not approved docetaxel as a treatment option for hormone sensitive prostate cancer. However, docetaxel is approved for advanced hormone resistant prostate cancer and other cancers. There is also evidence from a high quality, phase 3 randomized clinical trial supporting the use of docetaxel in metastatic hormone sensitive prostate cancer patients who have a high burden of metastasis. Docetaxel is an off-label indication for hormone sensitive prostate cancer.

The U.S. FDA has approved androgen deprivation therapy (ADT) agents, including leuprolide (Lupron), goserelin acetate (Zoladex), or degarelix (Firmagon), as a treatment option for hormone sensitive prostate cancer.

The combination of ADT, also called hormonal therapy, with docetaxel chemotherapy and nivolumab immunotherapy is considered investigational. ADT cuts off the supply of testosterone and is the standard of care for hormone sensitive prostate cancer. The addition of docetaxel chemotherapy has been found to prolong life for prostate cancer patients starting hormonal therapy for the first time for metastatic disease, who also have a large volume of cancer.

Another anti-cancer treatment modality is called immunotherapy. The immune system can kill cells that are recognized as different or dangerous, such as infected cells and cancer cells. Nivolumab is an antibody (a type of human protein) that work to stimulate the body's immune system to recognize and fight cancer cells.

Hormonal therapy and chemotherapy may make cancer cells more recognizable to the immune system, and make cancer cells more susceptible to immunotherapy. The goal of this study is to examine the activity and safety of hormonal therapy combined with docetaxel chemotherapy and nivolumab immunotherapy for hormone sensitive prostate cancer. The study is designed to enrich for patients whose tumors may be more most responsive to this treatment strategy. All patients will receive the same treatment of ADT combined with docetaxel chemotherapy and nivolumab immunotherapy.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2 Multicohort Study of Nivolumab in Combination With Docetaxel and Androgen Deprivation Therapy in Metastatic Hormone Sensitive Prostate Cancer Patients With DNA Damage Repair Defects or Inflamed Tumors
Actual Study Start Date : February 14, 2020
Estimated Primary Completion Date : June 30, 2023
Estimated Study Completion Date : June 30, 2025

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: COHORT 1: DNA damage repair defects (DDRD) +/- Inflamed Tumor

After the screening procedures confirm participation in the research study. The participant will be given a study calendar for this trial.

  • Androgen Deprivation Therapy: Given per standard care for duration of study
  • Nivolumab: Given once per every 3 weeks for cycle 1-6 intravenously and then every 4 weeks during subsequent cycles, at predetermined dosage
  • Docetaxel: Given once every 3 weeks intravenously at pre-determined dosage for cycle 1-6.
Drug: Androgen Deprivation Therapy
Given per standard care for duration of study. Regimens include Leuprolide (Lupron Depot) intramuscularly every 3 months, Goserelin acetate (Zoladex) subcutaneously every 4 weeks, or degarelix (Firmagon) subcutaneously every month per standard of care.
Other Names:
  • Leuprolide
  • Lupron Depot
  • Goserelin acetate
  • Zoladex
  • Degarelix
  • Firmagon

Drug: Nivolumab
Given once per every 3 weeks for cycle 1-6 intravenously and then every 4 weeks during subsequent cycles, at predetermined dosage; up to 28 cycles total.

Drug: Docetaxel
Given once every 3 weeks intravenously at pre determined dosage for cycle 1-6.
Other Name: Taxotere

Experimental: COHORT 2: Inflamed Tumor without DNA repair defects (DDRD)

After the screening procedures confirm participation in the research study. The participant will be given a study calendar for this trial.

  • Androgen Deprivation Therapy: Given per standard care for duration of study
  • Nivolumab: Given once per every 3 weeks for cycle 1-6 intravenously and then every 4 weeks during subsequent cycles, at predetermined dosage
  • Docetaxel: Given once every 3 weeks intravenously at pre-determined dosage for cycle 1-6.
Drug: Androgen Deprivation Therapy
Given per standard care for duration of study. Regimens include Leuprolide (Lupron Depot) intramuscularly every 3 months, Goserelin acetate (Zoladex) subcutaneously every 4 weeks, or degarelix (Firmagon) subcutaneously every month per standard of care.
Other Names:
  • Leuprolide
  • Lupron Depot
  • Goserelin acetate
  • Zoladex
  • Degarelix
  • Firmagon

Drug: Nivolumab
Given once per every 3 weeks for cycle 1-6 intravenously and then every 4 weeks during subsequent cycles, at predetermined dosage; up to 28 cycles total.

Drug: Docetaxel
Given once every 3 weeks intravenously at pre determined dosage for cycle 1-6.
Other Name: Taxotere

Experimental: COHORT 3: Biomarker Negative

After the screening procedures confirm participation in the research study. The participant will be given a study calendar for this trial.

  • Androgen Deprivation Therapy: Given per standard care for duration of study
  • Nivolumab: Given once per every 3 weeks for cycle 1-6 intravenously and then every 4 weeks during subsequent cycles, at predetermined dosage
  • Docetaxel: Given once every 3 weeks intravenously at pre-determined dosage for cycle 1-6
Drug: Androgen Deprivation Therapy
Given per standard care for duration of study. Regimens include Leuprolide (Lupron Depot) intramuscularly every 3 months, Goserelin acetate (Zoladex) subcutaneously every 4 weeks, or degarelix (Firmagon) subcutaneously every month per standard of care.
Other Names:
  • Leuprolide
  • Lupron Depot
  • Goserelin acetate
  • Zoladex
  • Degarelix
  • Firmagon

Drug: Nivolumab
Given once per every 3 weeks for cycle 1-6 intravenously and then every 4 weeks during subsequent cycles, at predetermined dosage; up to 28 cycles total.

Drug: Docetaxel
Given once every 3 weeks intravenously at pre determined dosage for cycle 1-6.
Other Name: Taxotere




Primary Outcome Measures :
  1. Number of patients with PSA ≤ 0.2 ng/mL at 12-months [ Time Frame: 1 year ]
    Summarized with 80% two-sided exact binominal confidence interval (CI)


Secondary Outcome Measures :
  1. Rate of PSA ≤ 0.2 ng/mL at 7 months [ Time Frame: Baseline to 7 months ]
    95% two-sided exact binomial CI

  2. Objective response rate [ Time Frame: 7 months from start of treatment ]
    95% two-sided exact binomial CI (per RECIST 1.1 criteria)

  3. Overall survival rate [ Time Frame: Time from start of treatment to death due to any cause, or censored at date last known alive up to 100 months ]
    Kaplan-Meier methodology

  4. Time to castration resistant disease [ Time Frame: Registration to date of documented clinical or serological progression with castrate-level testosterone level (<50 ng/dL) ]
    Kaplan-Meier methodology

  5. Time to clinical progression [ Time Frame: Baseline to documented clinical progression up to 100 months ]
    Kaplan-Meier methodology Defined as the time from registration to date of documented clinical progression, defined by increasing symptomatic bony metastasis, progression per RECIST 1.1 criteria, or clinical deterioration due to cancer based on investigator's judgment.

  6. Time to serologic progression [ Time Frame: Time from registration to the date of documented at least 50% increase in serum PSA, with the lowest PSA level (nadir) ]
    Kaplan-Meier methodology Time from registration to the date of documented at least 50% increase in serum PSA, with the lowest PSA level (nadir)

  7. Number of participants with severe adverse events as assessed by CTCAE v5.0 [ Time Frame: 28 cycles ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Newly diagnosed histologically confirmed prostate adenocarcinoma within 4 months prior to study registration with evidence of distant metastasis on conventional imaging

    • Distant metastasis is defined by non-regional lymph node(s) metastasis (M1a), bone metastasis (M1b), and/or other site(s) of metastatic disease (M1c).
    • Conventional imaging consists of CT, MRI or radionuclide bone scan.
  • Age ≥18 years
  • ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)

    o Participants with ECOG performance status of 2 are only eligible if the performance status decline is attributed to metastatic prostate cancer

  • Serum PSA > 4.0 ng/mL before initiation of ADT
  • Serum testosterone > 100 ng/dL before initiation of ADT

    o Participants whose testosterone level is unknown before initiation of ADT may be allowed after discussion with Sponsor-Investigator.

  • Grade ≤ 1 peripheral neuropathy, defined as asymptomatic or paresthesia and/or decreased deep tendon reflexes is allowed.
  • Participants must have adequate organ and marrow function as defined below:

    • Absolute neutrophil count ≥1,500 /mcL
    • Platelets ≥100,000 /mcL
    • Total bilirubin ≤1.5 × institutional upper limit of normal. Exception: Participants with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology) may be allowed after consultation with treating physician.
    • AST(SGOT) and ALT(SGPT) ≤2.5 × institutional upper limit of normal. Exception: ≤5 x institutional upper limit of normal in participants with liver metastasis.
    • Creatinine (Cr) and creatinine clearance (CrCl) Cr <1.6 mg/dL or CrCl ≥30 mL/min CrCl should be calculated using the Cockcroft-Gault formula
    • PT, INR and PTT ≤ 1.5 x institutional upper limit of normal. Exception: Participants who are on a stable regimen of therapeutic anticoagulation for an appropriate clinical indication may be enrolled
  • Availability of adequate baseline prostate biopsy tissue for integral biomarker analysis and correlative studies, defined as:

    • At least ten 5-micron formalin-fixed paraffin-embedded (FFPE) slides with unstained, freshly cut, serial sections from biopsy cores containing at least 20% tumor involvement with the highest Gleason score(s) for OncoPanel analysis is required
    • At least one 5-micron FFPE slide with unstained, freshly cut, serial sections from biopsy cores containing at least 50% tumor involvement with the highest Gleason score(s) for ImmunoProfile analysis is required. If slide with 50% tumor involvement is unavailable, a 5-micron slide containing at least 30% tumor will be accepted.
    • If archival FFPE tissue is unavailable or insufficient for OncoPanel and ImmunoProfile analysis, participants must be undergoing a standard of care prostate biopsy that will provide material meeting the above requirements in order to be eligible.
  • Successful OncoPanel and ImmunoProfile biomarker analysis using baseline prostate biopsy tissue for allocation into a study cohort during pre-screening

    • Participants whose tumors harbor somatic or germline homozygous deletions and/or deleterious mutations in a DDR gene using OncoPanel will be assigned to Cohort 1, regardless of ImmunoProfile results
    • Participants whose tumors are PD-L1 positive and/or CD8+ T cell inflamed using ImmunoProfile without the presence of DDRD will be assigned to Cohort 2
    • Participants whose tumors do not harbor DDRD and are PD-L1 negative with low CD8+ T cell infiltration will be assigned to Cohort 3
  • Willingness to provide leftover metastatic biopsy tissue for correlative studies, if obtained for clinical purposes
  • Based on its mechanism of action and data from animal studies, nivolumab can cause fetal harm. For this reason non-sterilized men who are sexually active with a female partner of childbearing potential treated or enrolled on this protocol must agree to use adequate contraception prior to the study, for the duration of study participation, and for 7 months after last dose of nivolumab administration
  • Ability to understand and the willingness to sign a written informed consent document, or have a legally authorized representative sign on the subject's behalf

Exclusion Criteria:

  • Participants must not have received prior ADT (LHRH analogue antiandrogen), chemotherapy, or immunotherapy for prostate cancer. The following exception is allowed:

    • Participants who have initiated ADT prior to study registration and are able to complete biomarker pre-screening, cohort allocation, and start C1D1 study chemoimmunotherapy ≤120 days from initiation of ADT are allowed
    • Antiandrogens (e.g., bicalutamide or flutamide) may be used in addition to LHRH analogue ≤28 days before initiation of LHRH analogue to cover the testosterone surge associated with certain LHRH agonists but must be discontinued prior to study registration
    • Second-generation hormonal agents (e.g., abiraterone acetate) are not allowed
  • Participants must not have undergone prostatectomy

    • Prostate radiation is allowed before or after study enrollment and may be delivered concurrently with study chemoimmunotherapy, per provider discretion, assuming adequate prostate biopsy tissue is collected before prostatic radiation
    • Metastasis-directed radiation is allowed before or after study enrollment and may be delivered concurrently with study chemoimmunotherapy, per provider discretion
  • Participants who are receiving any other investigational agents
  • Any previous treatment with a PD-1 or PD-L1 inhibitor
  • Participants with known brain metastases
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to docetaxel (including any drugs formulated with polysorbate 80), nivolumab, or LHRH analogue (e.g., leuprolide, goserelin acetate, degarelix)
  • History of another primary malignancy, except for:

    • Malignancy treated with curative intent and with no known active disease for ≥2 years before the first dose of study treatment and of low potential risk for recurrence
    • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Major surgical procedure as defined by the Site Investigator within 28 days prior to the first dose of chemoimmunotherapy
  • Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome.
  • History of allogeneic bone marrow or organ transplantation
  • Active or prior documented autoimmune or inflammatory disorders, including inflammatory bowel disease (e.g., Crohn's disease), systemic lupus erythematosus, Sarcoidosis syndrome, Grave's disease, rheumatoid arthritis, hypophysitis, uveitis, with the following exceptions:

    • Vitiligo or alopecia
    • Hypothyroidism stable on hormone replacement
    • Chronic skin condition that does not require systemic therapy
    • Celiac disease controlled by diet alone
    • Participants with inactive disease in the last 5 years may be included but only after consultation with the study physician
  • Active infection including tuberculosis, hepatitis B (known positive HBV surface antigen [HBsAg]), or hepatitis C (HCV)

    • Participants with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible
    • Participants with positive HCV antibody are eligible if polymerase chain reaction is negative for HCV RNA
  • Concurrent or prior use of immunosuppressive medication within 14 days before the first dose of study chemoimmunotherapy, with the following exceptions:

    • Premedication for docetaxel with dexamethasone prior to docetaxel administration
    • Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intraarticular injection)
    • Systemic corticosteroids at physiologic doses not exceeding 10mg/day of prednisone or its equivalent
    • Steroids as premedication for hypersensitivity reactions (e.g., premedication for iodinated contrast allergy before CT scan)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04126070


Contacts
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Contact: Xiao X Wei, MD (617) 632-4524 xiaox_wei@dfci.harvard.edu

Locations
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United States, Massachusetts
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02115
Contact: Xiao X Wei, MD         
Principal Investigator: Xiao X Wei, MD         
Beth Israel Deaconess Medical Center Recruiting
Boston, Massachusetts, United States, 02215
Contact: David J. Einstein, MD    617-667-2100    deinstei@bidmc.harvard.edu   
Principal Investigator: David J. Einstein, MD         
Sponsors and Collaborators
Xiao X. Wei
Bristol-Myers Squibb
Investigators
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Principal Investigator: Xiao X Wei, MD Dana-Farber Cancer Institute

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Responsible Party: Xiao X. Wei, Sponsor Investigator, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier: NCT04126070    
Other Study ID Numbers: 19-384
First Posted: October 14, 2019    Key Record Dates
Last Update Posted: March 4, 2020
Last Verified: March 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame: Data can be shared no earlier than 1 year following the date of publication
Access Criteria: DFCI - Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Xiao X. Wei, Dana-Farber Cancer Institute:
Hormone Sensitive Prostate Cancer
Prostate Adenocarcinoma
Metastasis Prostate Adenocarcinoma
Additional relevant MeSH terms:
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Prostatic Neoplasms
Adenocarcinoma
Neoplasm Metastasis
Hypersensitivity
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Genital Diseases, Male
Prostatic Diseases
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplastic Processes
Pathologic Processes
Immune System Diseases
Docetaxel
Nivolumab
Leuprolide
Goserelin
Androgens
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Immunological