A Multicenter Study Evaluating the Efficacy and Safety of Nivolumab and Ipilimumab in Combination With NP-101 Versus Placebo in Refractory Advanced and Metastatic Gastroenteropancreatic Neuroendocrine Carcinomas (GEP-NECs)

Inclusion Criteria:

• Age >18 years.

• Participants must have histologically or cytologically confirmed relapsed and/or refractory unresectable advanced and/or metastatic high-grade gastroenteropancreatic neuroendocrine carcinoma (GEP-NECs) and have failed at least one line of therapy.

• Participants must have received at least one prior therapy for this disease, including platinum therapy. Participants must have recovered from acute toxicities of prior chemotherapy. Any prior non-hematologic vital organ toxicity (cardiac, pulmonary, hepatic, and renal) of previous therapy must have resolved to grade 1 or less. Neurological toxicities must have resolved to grade 2 or less.

• Participants must have radiologic disease measurable by RECIST v1.1 criteria.

• All previous chemotherapy, investigational drugs, or radiation must be completed at least three weeks prior to starting study treatment.

• Performance status ECOG Performance status ≤ 2

• Participants must have adequate organ and marrow function as defined by all the below parameters:

  • Hemoglobin ≥8.0g/dl
  • Absolute neutrophil count ≥1,000/µcL
  • Platelet count ≥70,000/µcL
  • Total bilirubin < 1.5 X institutional upper limit of normal (IULN).
  • AST (SGOT) ≤ 3 X IULN.
  • ALT (SGPT) ≤ 3 X IULN.
  • AST or ALT ≤ 5 × ULN for participants with liver metastases.
  • Calculated creatinine clearance ≥ 45 mL/min.
  • Serum albumin ≥ 25 g/L (2.5 g/dL)

• Participants must have the ability to understand and the willingness to sign a written informed consent document.

• Female participants of childbearing potential and male participants with a partner of childbearing potential must agree to practice reliable contraception or to practice abstinence for at least 28 days before starting treatment and for at least 60 days after the last dose of NP-101, and for at least 5 months after last dose of nivolumab and for at least 3 months after the last dose of ipilimumab, whichever is later. Reliable contraception is defined as:

One highly effective method and one additional effective (barrier) method:

Examples of highly effective methods:

• Intrauterine device (IUD)
• Hormonal (injections, implants, levonorgestrel releasing intrauterine system [IUS], medroxyprogesterone acetate depot injections, ovulation inhibitory progesterone-only pills [e.g., desogestrel])
• Tubal ligation
• Partner's vasectomy

Examples of additional effective methods:

• Male condom

• Diaphragm

• Cervical Cap

• Participants must agree to not donate eggs or sperm starting at screening and throughout the study period, and for at least 60 days after the last dose of NP-101, and for at least 5 months after the last dose of nivolumab and for at least 3 months after the last dose of ipilimumab, whichever is later The presence of any of the following will exclude a participant from study enrollment.

  • Pulmonary neuroendocrine carcinoma (Small cell or non-small cell) are excluded from this trial.
  • Well differentiated GEP-NETs are excluded from this trial.
  • Prior treatment toxicities that have not resolved to ≤ Grade 2 according to NCI CTCAE Version 5.0 (list exceptions, e.g. alopecia, neuropathy, etc.).
  • Participants received prior nivolumab or ipilimumab.
  • Participants with untreated brain metastases/CNS disease will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Participants with treated CNS metastases will be considered for the study.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to NP-101 or immunotherapy (nivolumab or ipilimumab) used in this study.
  • Participants with 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.
  • QT interval on an electrocardiogram (ECG) corrected for heart rate using Fridericia's formula (QTcF) > 470 ms (males) or > 480 ms (females) at screening (any 2 of 3 triplicate ECGs)
  • Solid organ or allogeneic hematopoietic stem cell transplant recipients.
  • Participants with significant autoimmune disease requiring immunosuppressive treatment, and participants with active interstitial lung disease or pneumonitis.
  • Participants who have a diagnosis of immunodeficiency or are receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. The use of physiological doses of corticosteroids may be approved after consultation with the Sponsor. Examples of physiological doses of steroids include: Hydrocortisone: 10-25 mg total daily dose, Prednisone or Prednisolone: 4-10 mg daily, and Methylprednisolone: 3-5 mg daily.
  • Pregnant or breastfeeding women are excluded from this study.
  • Known chronic active untreated hepatitis B or C infection.
  • HIV-positive participants on combination antiretroviral therapy.
  • Participants with inflammatory bowel disease (such as Crohn's) that could affect the intestinal absorption of NP-101 capsules
  • Current use, or use within 14 days prior to first dose (or [5 half-lives / documented induction offset period], whichever is longer), of any strong or moderate inducer of CYP3A4, CYP1A2, CYP2C9, or CYP2D6, including but not limited to those listed in Table 7
  • Current use of any medication that is a sensitive substrate of CYP2C9, CYP3A4, CYP1A2, or CYP2D6 with a narrow therapeutic index (including but not limited to warfarin, phenytoin, and other agents listed in Table 8), unless an alternative non-interacting agent is available, or unless the Investigator/Medical Monitor determines the patient can be safely managed with enhanced monitoring (e.g., INR monitoring for warfarin, therapeutic drug level monitoring for phenytoin)

Exclusion Criteria:

• The presence of any of the following will exclude a participant from study enrollment.

  • Pulmonary neuroendocrine carcinoma (Small cell or non-small cell) are excluded from this trial.
  • Well differentiated GEP-NETs are excluded from this trial.
  • Prior treatment toxicities that have not resolved to ≤ Grade 2 according to NCI CTCAE Version 5.0 (list exceptions, e.g. alopecia, neuropathy, etc.).
  • Participants received prior nivolumab or ipilimumab.
  • Participants with untreated brain metastases/CNS disease will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Participants with treated CNS metastases will be considered for the study.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to NP-101 or immunotherapy (nivolumab or ipilimumab) used in this study.
  • Participants with 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.
  • QT interval on an electrocardiogram (ECG) corrected for heart rate using Fridericia's formula (QTcF) > 470 ms (males) or > 480 ms (females) at screening (any 2 of 3 triplicate ECGs)
  • Solid organ or allogeneic hematopoietic stem cell transplant recipients.
  • Participants with significant autoimmune disease requiring immunosuppressive treatment, and participants with active interstitial lung disease or pneumonitis.
  • Participants who have a diagnosis of immunodeficiency or are receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. The use of physiological doses of corticosteroids may be approved after consultation with the Sponsor. Examples of physiological doses of steroids include: Hydrocortisone: 10-25 mg total daily dose, Prednisone or Prednisolone: 4-10 mg daily, and Methylprednisolone: 3-5 mg daily.
  • Pregnant or breastfeeding women are excluded from this study.
  • Known chronic active untreated hepatitis B or C infection.
  • HIV-positive participants on combination antiretroviral therapy.
  • Participants with inflammatory bowel disease (such as Crohn's) that could affect the intestinal absorption of NP-101 capsules
  • Current use, or use within 14 days prior to first dose (or [5 half-lives / documented induction offset period], whichever is longer), of any strong or moderate inducer of CYP3A4, CYP1A2, CYP2C9, or CYP2D6, including but not limited to those listed in Table 7
  • Current use of any medication that is a sensitive substrate of CYP2C9, CYP3A4, CYP1A2, or CYP2D6 with a narrow therapeutic index (including but not limited to warfarin, phenytoin, and other agents listed in Table 8), unless an alternative non-interacting agent is available, or unless the Investigator/Medical Monitor determines the patient can be safely managed with enhanced monitoring (e.g., INR monitoring for warfarin, therapeutic drug level monitoring for phenytoin)