A Study of Chemoimmunotherapy for the Treatment of Men With Neuroendocrine or Aggressive Variant Metastatic Prostate Cancer
A Study of Chemoimmunotherapy for the Treatment of Men With Neuroendocrine or Aggressive Variant Metastatic Prostate Cancer
The purpose of this study is to evaluate the safety and efficacy of a combination of
 nivolumab, ipilimumab, cabazitaxel and carboplatin in men with neuroendocrine prostate cancer
 (NEPC) or other aggressive variants of prostate cancer (AVPC). This study will also
 investigate biomarkers to gain a better understanding of how the drug combination of
 nivolumab, ipilimumab, cabazitaxel and carboplatin affects these types of prostate cancer and
 the immune system. Eligible subjects will receive up to 10 cycles of nivolumab, ipilimumab,
 carboplatin and cabazitaxel followed by maintenance nivolumab and ipilimumab. Subjects may
 continue receiving study drugs until cancer progression, severe toxicity, withdrawal of
 consent, 3 years from the initial dose of study drugs or study termination, whichever occurs
 earlier. Subjects will be followed for 3 years from the initial dose of study drugs.
Inclusion Criteria:

 1. Neuroendocrine-like prostate cancer, based on histology OR based on clinical
 presentation as defined by meeting one of the two below criteria. All subjects must
 submit their primary tumor or metastatic biopsy pathology specimens to the Duke Cancer
 Institute where they will be centrally reviewed by Duke Pathology. Central Duke
 pathologic review is not required for screening but rather for confirmation of
 histologic subtype. Local pathologic review is sufficient for eligibility
 determination.

 1. Criterion 1: Presence of 1 of 3 histologically proven diagnoses: 1) Primary small
 cell carcinoma of the prostate, defined by classic histologic features such as
 small tumor cells with scanty cytoplasm, darkly stained nuclei with homogeneous
 chromatin pattern. The tumor cells do not form glandular structure but grow as
 solid sheets with frequent mitotic figures and necrosis; 2) Intermediate atypical
 carcinoma of the prostate, which has histologic features distinct from small cell
 carcinoma or adenocarcinoma. The tumor grows as solid sheets or vague glandular
 structures. The tumor cells have moderate amounts of cytoplasm and centrally
 located, round and regular nuclei with fine, granular and homogeneous chromatin.
 Mitosis and necrosis are absent; 3) mixed histology tumors of the prostate,
 containing both adenocarcinoma and neuroendocrine or small cell components.

 2. Criterion 2: Presence of histologically proven adenocarcinoma of the prostate
 without any sign of neuroendocrine or small cell histology that is
 radiographically progressing despite castrate levels of testosterone (<50 ng/mL)
 with the following poor risk features:

 i. Prior progression despite therapy with either abiraterone acetate and/or
 enzalutamide.

 ii. At least one of the following: 1) Visceral metastases; 3) Bulky lymphadenopathy or
 pelvic mass (>5 cm); 4) Low PSA (<10 ng/mL) with high volume (>20) bone metastases; 5)
 Short interval (<6mo) to CRPC following initiation of hormonal therapy 6) Pathogenic
 alterations in two of the three following genes: TP53, RB1, and PTEN as determined by
 tissue or plasma tumor DNA commercial or academic assays. 7) Predominantly lytic bone
 metastases on imaging, 8) Presence of neuroendocrine markers on histology (positive
 staining of chromogranin A or synaptophysin) or in serum (abnormal high serum levels
 for chromogranin A or GRP) at initial diagnosis or at progression. Plus any of the
 following in the absence of other causes: A. elevated serum LDH (>= IULN); B.
 malignant hypercalcemia; C. elevated serum CEA (>2x IULN).

 2. Available archival tumor tissue for pathologic review and correlative studies. Tumor
 tissue (localized or metastatic) does not need to be received but rather identified
 and available (slides and/or blocks) to be sent to Duke.

 3. Documented progressive metastatic CRPC as determined by the provider based on at least
 one of the following criteria:

 1. PSA progression defined as 25% increase over baseline value with an increase in
 the absolute value of at least 2.0 ng/mL that is confirmed by another PSA level
 with a minimum of a 1 week interval and a minimum PSA of 2.0 ng/mL. Note: If
 confirmed rise is the only indication of progression, a minimal starting value of
 1.0 ng/mL is acceptable, unless pure small-cell carcinoma.

 2. Soft-tissue progression based on new lesions or growth of existing soft tissue
 metastases.

 3. Progression of bone metastasis with one or more new bone lesion(s) by imaging.

 4. Castrate levels of serum total testosterone (<50 ng/dl) OR ongoing documented ADT
 unless pure small cell prostate cancer is present.

 5. Karnofsky performance status of 70 or higher.

 6. Acceptable initial laboratory values within 14 days of Cycle 1 Day 1

 7. Age >18

 8. Subjects with a partner who is a woman of child-bearing potential must agree to use
 one form of highly effective contraception as detailed in Section 8.3 of this protocol
 during the treatment period with cabazitaxel and for 3 months after the last dose of
 cabazitaxel and during the treatment period with nivolumab and for 7 months after the
 last dose of nivolumab, whichever is later. Subjects receiving cabazitaxel or
 nivolumab must also refrain from donating sperm during this period.

 9. Willing and able to provide written informed consent and HIPAA authorization for the
 release of personal health information.

 10. Life expectancy of over 3 months as determined by treating physician.

 Exclusion Criteria:

 1. Prior use of abiraterone or androgen receptor antagonists (ie enzalutamide) used to
 treat prostate cancer are permitted but should be stopped two or more weeks prior to
 study treatment initiation.

 2. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with
 an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4,
 OX 40, CD137).

 3. Has received other prior systemic anti-cancer therapy including investigational agents
 within 4 weeks prior to study treatment initiation

 4. Prior receipt of cabazitaxel chemotherapy or 2 or more chemotherapy regimens. One
 prior chemotherapy regimen including docetaxel or platinum-containing chemotherapy is
 permitted.

 5. Has received prior radiotherapy within 2 weeks of start of study intervention.
 Participants must have recovered from all radiation-related toxicities, not require
 corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted
 for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.

 6. Has received a live vaccine within 30 days prior to the first dose of study drug.
 Examples of live vaccines include, but are not limited to, the following: measles,
 mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
 Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
 are generally killed virus vaccines and are allowed; however, intranasal influenza
 vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.

 7. Is currently participating in or has participated in a study of an investigational
 agent or has used an investigational device within 4 weeks prior to the first dose of
 study intervention.

 8. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
 (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
 immunosuppressive therapy within 7 days prior to the first dose of study drug.

 9. Has a history of a second malignancy, unless potentially curative treatment has been
 completed with no evidence of malignancy for 2 years.

 10. Has known active untreated CNS metastases and/or carcinomatous meningitis.
 Participants with previously treated brain metastases may participate provided they
 are radiologically stable, i.e. without evidence of progression for at least 4 weeks
 by repeat imaging (note that the repeat imaging should be performed during study
 screening), clinically stable and without requirement of steroid treatment greater
 than prednisone 10mg (or equivalent) for at least 14 days prior to first dose of study
 intervention.

 11. Has active autoimmune disease that has required systemic treatment in the past 2 years
 (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
 drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid
 replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
 form of systemic treatment and is allowed.

 12. Has a history of (non-infectious) pneumonitis that required steroids or has current
 pneumonitis.

 13. Has an active infection requiring systemic therapy.

 14. Has a known uncontrolled Human Immunodeficiency Virus (HIV) infection based on
 detectable HIV viral load and abnormal CD4 count of <350/mm3.

 15. Has a known active Hepatitis B (defined as Hepatitis B surface antigen [HBsAg]
 reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is
 detected) infection.

 16. Has a known active TB (Bacillus Tuberculosis) infection.

 17. Has a history or current evidence of any condition, therapy, or laboratory abnormality
 that might confound the results of the study, interfere with the subject's
 participation for the full duration of the study, or is not in the best interest of
 the subject to participate, in the opinion of the treating investigator.

 18. Has known current psychiatric or substance abuse disorders that would interfere with
 cooperation with the requirements of the trial.

 19. Has had an allogenic tissue/solid organ transplant.