MC# 20-13

1. Must be ≥18 years on the day of signing informed consent
2. Be willing and able to provide written informed consent/assent for the study
3. Subjects with histologically or cytologically confirmed advanced or metastatic solid tumors who have disease progression after treatment with all available therapies for metastatic disease that are known to confer clinical benefit, or are intolerant to treatment, or refuse standard treatment
4. Have measurable disease per RECIST v1.1 as assessed by the enrolling physician.  Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
5. Subjects enrolling in the Phase 1b and Arms I, IVa, V, and Va of the Phase 2a, and the Biomarker Cohort must have biopsiable disease (i.e., have at least 1 tumor lesion that is accessible and feasible for biopsy) as determined by the enrolling physician.  Willing to provide archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated.  Formalin-fixed, paraffin embedded (FFPE) tissue block is preferred to slide.  Newly obtained biopsy is preferred to archived tissue.
6. Eastern Cooperative Oncology Group (ECOG) performance status 0-1
7. Subjects must have a life expectancy of greater than or equal to 12 weeks per assessment from the enrolling physician
8. Subjects must have adequate organ function as defined below:
   • Absolute neutrophil count ≥1,500/µL
   • Platelets ≥100,000/µL
   • Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/L (Criteria must be met without erythropoietin dependency and without packed red blood cell transfusion within last 2 weeks)
   • Total bilirubin ≤1.5 × institutional upper limit of normal (ULN) OR direct bilirubin ≤ULN for subjects with total bilirubin levels >1.5 × ULN
   • AST(SGOT)/ALT(SGPT) ≤2.5 × ULN (AST and/or ALT ≤5 × ULN for subjects with liver metastasis)
   • Alkaline phosphatase ≤2.5 × ULN (≤5 × ULN for subjects with documented liver involvement or bone metastases)
   • Creatinine ≤1.5 × ULN or Creatinine clearance (CrCl) ≥30 mL/min for subject with creatinine levels >1.5 × ULN.  CrCl should be calculated per institutional standard.
   • INR and aPTT ≤1.5 × ULN unless subject is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
9. Female subjects who are either postmenopausal for at least 1 year, are surgically sterile for at least 6 weeks; female subjects of childbearing potential must agree to remain abstinent (refrain from heterosexual intercourse) or to use dual methods of contraception for the duration of study treatment and for 120 days after the last dose of study treatment (pembrolizumab and/or NT-I7).  Female subjects of childbearing potential (including women who have had a tubal ligation) must have a negative serum or urine pregnancy test within 72 hours prior to Cycle 1, Day 1.  If the urine test is positive, or cannot be confirmed as negative, a serum pregnancy test will be required.
10. Non-sterile male subjects who are sexually active with female partners of childbearing potential must agree to remain abstinent (refrain from heterosexual intercourse) or to use highly effective method(s) of contraception for the duration of study treatment and for 120 days after the last dose of study treatment (pembrolizumab and/or NT-I7)
11. And meet the requirements for the intended stages and arms (disease specific inclusion criteria), as following:

Applicable to the Dose escalation phase (Phase 1b) only:

• Relapsed/refractory advanced solid tumors.  Note: Prior anti-PD-1/anti-PD-L1 requires a 4-week washout period.
• Willing to provide pre- and on-treatment biopsies

Applicable to the Dose expansion phase (Phase 2a) only:

Anti-PD-1/anti-PD-L1 refractory criteria for CPI-treated TNBC, NSCLC, and SCLC

Subjects must have progressed on treatment with an anti-PD-1/anti-PD-L1 monoclonal antibody (mAb) administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies. PD-1/PD-L1 treatment progression is defined by meeting all of the following criteria:

• Has received at least 2 doses of an approved anti-PD-1/anti-PD-L1 mAb.  Note: Prior anti-PD-1/anti-PD-L1 requires a 4-week washout period.
• Has demonstrated disease progression after anti-PD-1/anti-PD-L1 treatment as defined by RECIST v1.1.  The initial evidence of disease progression (PD) is to be confirmed by a second assessment no less than four weeks from the date of the first documented PD, in the absence of rapid clinical progression.  Note: This determination is made by the investigator. Once PD is confirmed, the initial date of PD documentation will be considered the date of disease progression.
• Progressive disease has been documented within 12 weeks from the last dose of anti-PD- 1/anti-PD-L1 mAb

Specific to Arm I: CPI treated R/R TNBC

• Histopathologic or cytologic documented TNBC.  Tumors must have been confirmed negative for ER and PR by IHC (<1% positive tumor nuclei, as per ASCO-CAP guideline recommendations) and negative for HER2 by IHC or fluorescent or chromogenic in situ hybridization (FISH or CISH).
• Received one or more prior therapies for TNBC in the advanced or metastatic setting, and prior treatment (for advanced, metastatic or (neo) adjuvant) must have included a taxane and/or anthracycline-based therapy and anti-PD-1/anti-PD-L1.
• Willing to provide pre- and on-treatment biopsies

Specific to Arm II: CPI treated R/R NSCLC

• Had prior treatment with CPI. Subjects with EGFR, BRAF, or ROS1 mutations or ALK translocations are required to have received prior therapy with the appropriate TKI; prior platinum-based chemotherapy is not required for this specific patient population

Specific to Arm III: CPI treated R/R SCLC

• Recurrent extensive-stage SCLC
• Received prior CPI therapy

Specific to Arm IV: CPI naïve R/R MSS-CRC

• MSS-CRC (categorized as MSS by immunohistochemistry (IHC) or polymerase chain reaction (PCR)-based local assay at any time prior to screening or by a central laboratory).  Note: Subjects with microsatellite instability-high (MSI-H) or microsatellite unstable CRC are not eligible.
• Previously treated with standard therapies, which must include fluoropyrimidine, oxaliplatin, and irinotecan; subjects treated with CPI are not eligible
• Willing to provide pre- and on-treatment biopsies

Specific to Arm IVa: CPI naïve R/R MSS-CRC

• MSS-CRC (categorized as MSS by immunohistochemistry (IHC) or polymerase chain reaction (PCR)-based local assay at any time prior to screening or by a central laboratory).  Note: Subjects with microsatellite instability-high (MSI-H) or microsatellite unstable CRC are not eligible.
• Previously treated with standard therapies, which must include fluoropyrimidine, oxaliplatin, and irinotecan; subjects treated with CPI are not eligible
• Willing to provide pre- and on-treatment biopsies

Specific to Arm V: CPI naïve R/R Pancreatic Cancer

• Have documented radiographic progression to or documented intolerance of first line systemic chemotherapy which included either gemcitabine or Fluorouracil (5-FU) based regimen (including capecitabine); subjects treated previously with CPI are not eligible
• Willing to provide pre- and on-treatment biopsies

Specific to Arm Va: CPI naïve R/R Pancreatic Cancer

• Have documented radiographic progression to or documented intolerance of first line systemic chemotherapy which included either gemcitabine or Fluorouracil (5-FU) based regimen (including capecitabine); subjects treated previously with CPI are not eligible
• Willing to provide pre- and on-treatment biopsies

Applicable to Biomarker Cohort only:

• Specific to CPI naïve R/R Ovarian Cancer Up to 5 prior lines of treatment, including platinum-based treatment(s); subjects treated previously with CPI are not eligible
• Willing to provide pre- and on-treatment tumor biopsies.

1. Pregnant, lactating or breastfeeding or expecting to conceive or father children within the study duration from screening through 120 days after the last dose of study treatment.
2. Receiving any investigational therapy or any approved therapy for investigational use within 30 days or 5 half-lives, whichever is longer, prior to first dose of study treatment.  Note: All AEs related to previous therapies, except alopecia, must be resolved to ≤Grade 1 or baseline.  Subjects with ≤Grade 2 neuropathy may be eligible.  Subjects with endocrine-related AEs Grade <2 requiring treatment or hormone replacement may be eligible.
3. Has received prior radiotherapy within 2 weeks of start of study treatment.  Subjects 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.
4. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.  Subjects with previously treated brain metastases may participate provided they are radiologically stable (without evidence of progression by repeat imaging (during screening) for at least 4 weeks prior to the first dose of study treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 14 days prior to first dose of study treatment
5. Subjects who have not recovered from AEs (other than alopecia, vitiligo, neuropathy or endocrinopathy managed with replacement therapy) due to agents administered more than 4 weeks earlier (i.e., have residual toxicities >Grade 1)
6. Concurrent or previous other malignancy within 3 years of study entry, except cured basal or squamous cell skin cancer, transitional cell carcinoma of urothelial cancer, carcinoma in- situ of the breast or cervix
7. History of severe hypersensitivity reactions to monoclonal antibodies (mAbs) or intravenous immunoglobulin preparations; any history of anaphylaxis; prior history of human anti-human antibody response; known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.  Note: Subject with severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients are also excluded.
8. Subjects who have spinal cord compression not definitively treated with surgery and/or radiation or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for ≥2 weeks prior to screening
9. Subjects who have autoimmune disease history for the past 2 years, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Bell’s palsy, Guillain-Barre syndrome, multiple sclerosis, vasculitis or glomerulonephritis
10. Have active and clinically relevant bacterial, fungal, viral, or TB infection, including known Hepatitis A, B, or C or HIV (testing not required)
11. Clinically significant cardiac disease, including, but not limited to, any of the following: Congestive heart failure requiring treatment (New York Heart Association Grade ≥ 2); clinically significant and uncontrolled atrial fibrillation; history of acute coronary syndromes including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting < 6 months prior to screening; symptomatic chronic heart failure, history or current evidence of clinically significant cardiac arrhythmia and/or conduction abnormality < 6 months prior to screening except controlled atrial fibrillation and paroxysmal supraventricular tachycardia
12. Subjects who have received treatment with systemic immunosuppressive medications (including, but not limited to, prednisone >10 mg/day, cyclophosphamide, azathioprine, methotrexate, thalidomide and antitumor necrosis factor [anti-TNF] agents) within 7 days prior to first dose of study treatment.  Note: Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
13. History of allergy or intolerance (unacceptable AEs) to study drug components or polysorbate-80-containing infusions.  Note: Polysorbate 80 is a buffer used to make NT-I7.
14. Has a history of non-infectious pneumonitis that required steroids or current pneumonitis
15. 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 enrolling physician
16. Has a known psychiatric or substance abuse disorder that would interfere with the subject’s ability to cooperate with the requirements of the study
17. 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 (e.g., FluMist®) are live attenuated vaccines and are not allowed.
18. Has had an allogenic tissue/solid organ transplant or bone marrow transplant
19. 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 (e.g., CTLA-4, OX 40, CD137) and was discontinued from that treatment due to a Grade 3 or higher irAE