Clinical Trials /

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

NCT04126070

Description:

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

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab + Docetaxel + ADT in Metastatic Hormone Sensitive Prostate Cancer
  • 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

Clinical Trial IDs

  • ORG STUDY ID: 19-384
  • NCT ID: NCT04126070

Conditions

  • Hormone Sensitive Prostate Cancer
  • Prostate Adenocarcinoma
  • Metastasis Prostate Adenocarcinoma

Interventions

DrugSynonymsArms
Androgen Deprivation TherapyLeuprolide, Lupron Depot, Goserelin acetate, Zoladex, Degarelix, FirmagonCOHORT 1: DNA damage repair defects (DDRD) +/- Inflamed Tumor
NivolumabCOHORT 1: DNA damage repair defects (DDRD) +/- Inflamed Tumor
DocetaxelTaxotereCOHORT 1: DNA damage repair defects (DDRD) +/- Inflamed Tumor

Purpose

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

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.
    

Trial Arms

NameTypeDescriptionInterventions
COHORT 1: DNA damage repair defects (DDRD) +/- Inflamed TumorExperimentalAfter 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.
  • Androgen Deprivation Therapy
  • Nivolumab
  • Docetaxel
COHORT 2: IInflamed Tumor without DNA repair defects (DDRD)ExperimentalAfter 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.
  • Androgen Deprivation Therapy
  • Nivolumab
  • Docetaxel
COHORT 3: Biomarker NegativeExperimentalAfter 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
  • Androgen Deprivation Therapy
  • Nivolumab
  • Docetaxel

Eligibility 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)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of patients with PSA ≤ 0.2 ng/mL at 12-months
Time Frame:1 year
Safety Issue:
Description:Summarized with 80% two-sided exact binominal confidence interval (CI)

Secondary Outcome Measures

Measure:Rate of PSA ≤ 0.2 ng/mL at 7 months
Time Frame:Baseline to 7 months
Safety Issue:
Description:95% two-sided exact binomial CI
Measure:Objective response rate
Time Frame:7 months from start of treatment
Safety Issue:
Description:95% two-sided exact binomial CI (per RECIST 1.1 criteria)
Measure: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
Safety Issue:
Description:Kaplan-Meier methodology
Measure:Time to castration resistant disease
Time Frame:Registration to date of documented clinical or serological progression with castrate-level testosterone level (<50 ng/dL)
Safety Issue:
Description:Kaplan-Meier methodology
Measure:Time to clinical progression
Time Frame:Baseline to documented clinical progression up to 100 months
Safety Issue:
Description: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.
Measure: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)
Safety Issue:
Description:Kaplan-Meier methodology Time from registration to the date of documented at least 50% increase in serum PSA, with the lowest PSA level (nadir)
Measure:Number of participants with severe adverse events as assessed by CTCAE v5.0
Time Frame:28 cycles
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Xiao X. Wei

Trial Keywords

  • Hormone Sensitive Prostate Cancer
  • Prostate Adenocarcinoma
  • Metastasis Prostate Adenocarcinoma

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