A Study of DSP-7888 Dosing Emulsion in Combination With Immune Checkpoint Inhibitors in Adult Patients With Advanced Solid Tumors

This is a Phase 1b/2, open-label, multicenter study of DSP-7888 Dosing Emulsion in combination with checkpoint inhibitors (nivolumab or pembrolizumab) in adult patients with solid tumors, that consists of 2 parts: dose search part of the study (Phase 1b and Phase 1b Enrichment Cohort) and the dose expansion part of the study (Phase 2). In Phase 1b of this study there will be 2 arms: Arm 1 and Arm 2. In Arm 1, there will be 6 to 12 patients who will be dosed with DSP-7888 Dosing Emulsion and nivolumab and in Arm 2 there will be 6 to 12 patients who will be dosed with DSP-7888 Dosing Emulsion and pembrolizumab. In addition, an enrichment cohort of a further 10 patients who have locally advanced or metastatic Renal Cell Carcinoma or Urothelial Cancer with primary or acquired resistance to previous checkpoint inhibitors will be enrolled into Phase 1b of the study to help evaluate the preliminary antitumor activity of DSP-7888 Dosing Emulsion at the safe dose level identified in the dose-search part of the study, and will be dosed with DSP-7888 Dosing Emulsion and nivolumab, or DSP-7888 Dosing Emulsion and pembrolizumab, as per the investigator's preference. At the safe, recommended dose determined in Phase 1b, platinum-resistant ovarian cancer (PROC) patients will be enrolled in Phase 2 of the study with DSP-7888 Dosing Emulsion, exploring the combination with pembrolizumab (Arm 2). In Phase 2, approximately 40 patients with PROC will be initially enrolled; additional patients may be enrolled to further assess anti-tumor activities, but the total sample size will not exceed 60 patients. This brings the total maximum study population to approximately 84 patients.


Eligibility Criteria:
Inclusion Criteria Phase 1b:

Patients must fulfill each of the following requirements:

1. Phase 1b Dose Search Part Only: A histologically or cytologically confirmed cancer that is metastatic and is approved to be treated with nivolumab or pembrolizumab with the following origins:

   * Nivolumab: unresectable or metastatic melanoma, metastatic NSCLC, advanced RCC, recurrent or metastatic squamous cell carcinoma of the head and neck, locally advanced or metastatic urothelial carcinoma, hepatocellular carcinoma, MSI-H/dMMR colorectal cancer
   * Pembrolizumab: unresectable or metastatic melanoma, metastatic NSCLC, recurrent or metastatic squamous cell carcinoma of the head and neck, locally advanced or metastatic urothelial carcinoma, unresectable or metastatic MSI-H/dMMR solid tumors, recurrent locally advanced or metastatic gastric cancer or gastroesophageal junction adenocarcinoma, recurrent or metastatic cervical cancer

   In addition, the following requirements must be fulfilled:
   1. Patients must not be considered eligible for a potentially curative resection.
   2. Patients who are eligible for PD-1 therapy based on either criterion (i) or (ii) below:

   (i) Patients progressed on their prior treatment before initiating treatment on current study, OR (ii) Patients who are currently being treated with nivolumab or pembrolizumab and have achieved at least stable disease (SD), and who, in the judgment of their treating physicians, could benefit from the addition of DSP-7888 Dosing Emulsion vaccine to improve or maintain their response.

   Phase 1b Enrichment Cohort Only: Patients with locally advanced or metastatic RCC or urothelial carcinoma who have experienced disease progression per iRECIST (iCPD) during or within 3 months of last dose of the most recent prior anti-PD-1/ PD-L1-based treatment
2. Patients must be positive for at least 1 of the following human leukocyte antigens:

   1. HLA-A\*02:01
   2. HLA-A\*02:06
   3. HLA-A\*24:02
   4. HLA-A\*03:01
   5. HLA-B\*15:01
3. ≥ 18 years of age
4. Eastern Cooperative Oncology group (ECOG) performance status of 0 or 1
5. Patients must be able to provide archival tumor tissue with sufficient tumor tissue, or patients must consent to undergo tumor biopsy to acquire sufficient tissue before first administration of study
6. Females of childbearing potential must have a negative serum pregnancy test
7. Male or female patients of child-producing potential must agree to use contraception or use prevention of pregnancy measures (true abstinence) during the study and for 6 months (for females and males alike) after the last dose
8. Total bilirubin of ≤ 2.0 mg/dL (≤ 3.0 mg/dL for patients with known Gilbert's syndrome)
9. Aspartate aminotransferase (AST) ≤ 3.0 × the upper limit of normal (ULN) or \< 5 × ULN if considered to be due to liver metastases
10. Alanine transaminase (ALT) ≤ 3.0 × the upper limit of normal (ULN) or \< 5 × ULN if considered to be due to liver metastases
11. Glomerular Filtration Rate \> 40 mL/min
12. Multigated acquisition (MUGA) scan or echocardiogram with left ventricular ejection fraction (LVEF) \> 40%
13. Life expectancy ≥ 3 months
14. Patients must be willing to provide a signed and dated ICF

Exclusion Criteria Phase 1b:

Patients with any of the following will be excluded from the study:

1. Anticancer chemotherapy (including molecular targeted drugs), immunotherapy, radiotherapy, or investigational agents within 4 weeks of the first dose of DSP 7888 Dosing Emulsion
2. Major surgery within 4 weeks prior to study treatment
3. Patients who have received a live vaccine within 4 weeks prior to the first dose
4. Any known, untreated brain metastases; patients with treated brain metastases must be clinically stable for 4 weeks after completion of treatment for brain metastases and have radiographic image documentation of stability. Patients must have no clinical symptoms from brain metastases and not have required systemic corticosteroids \> 10 mg/day prednisone or equivalent for at least 2 weeks prior to the first dose of study drug
5. Patients who have multifocal glioblastoma
6. Pregnant or breastfeeding
7. Patients who have an active autoimmune disease requiring immunosuppression \> 10 mg/day prednisone or equivalent a. Patients with controlled hyperthyroidism must be negative for thyroglobulin and thyroid peroxidase antibodies and thyroid stimulating immunoglobulin prior to study drug administration
8. Patients who have interstitial lung disease or active, non-infectious pneumonitis
9. Known hypersensitivity to a component of protocol therapy:

   1. Patients with known hypersensitivity to any of the components of DSP-7888 Dosing Emulsion.
   2. Patients with known hypersensitivity to nivolumab or pembrolizumab are excluded from receiving combination therapy that includes the agent to which they are hypersensitive
10. Uncontrolled concurrent illness including, but not limited to: ongoing or active, uncontrolled bacterial, viral, or fungal infections requiring systemic therapy; clinically significant non-healing or healing wounds; symptomatic congestive heart failure; unstable angina pectoris; severe and/or uncontrolled cardiac arrhythmia; significant pulmonary disease; or, psychiatric illness/social situations that would limit compliance with study requirements
11. Patients with a history of another primary cancer with the exception of: (a) curatively resected non-melanoma skin cancer; (b) curatively treated cervical carcinoma in situ; (c) localized prostate cancer not requiring systemic therapy; and d) any another cancer from which the patient has been disease free for ≥ 2 years that, in the opinion of the Investigator and medical monitor for the Sponsor, will not affect patient outcome in the setting of the current diagnosis
12. Patients who have a QTcF (QT corrected based on Fridericia's equation) interval \> 480 msec (CTCAE = Grade 2) or other factors that increase the risk of QT prolongation or arrhythmic events (e.g. heart failure, hypokalemia, family history of long QT interval syndrome) at screening
13. Patients who have a medical history of frequent or sustained ventricular ectopy
14. Patients who have, in the opinion of the treating Investigator, any concurrent conditions that could pose an undue medical hazard or interfere with the interpretation of the study results
15. Known history of human immunodeficiency virus (HIV) infection, active hepatitis B, or untreated hepatitis C
16. Patients who have baseline signs and symptoms consistent with clinically significant, decreased pulmonary function: (1) blood saturation oxygen level (SpO2) \< 90% at rest on room air; (2) dyspnea at rest or required supplemental oxygen within 2 weeks of study enrollment

Inclusion Criteria Phase 2:

Patients eligible for inclusion must meet all of the following criteria:

1. Patients must be female ≥ 18 years of age, able to understand study procedures, and subsequently agreed to participate in the study by providing a written informed consent obtained prior to any prescreening and screening procedures that are not standard of care 2.

Patients must be positive for at least 1 of the following human leukocyte antigens (HLA):

a. HLA-A\*02:01 b. HLA-A\*02:06 c. HLA-A\*24:02 d. HLA-A\*03:01 e. HLA-B\*15:01

3. Patients must have histologically diagnosed ovarian, fallopian tube, or primary peritoneal cancer with predominantly high-grade (Grade 2 or 3) serous epithelial features 4. Patients must be considered platinum resistant to last administered platinum-based therapy, defined as patient relapsed within 6 months after last dose of platinum-based therapy 5. Patients must have completed at least 1 but no more than 4 prior lines of therapy for serous epithelial ovarian, fallopian tube, or primary peritoneal cancer;

1. Maintenance is not considered a separate line of treatment (even if patients with BRCA mutation positive received PARP-inhibitor following induction therapy with a platinum doublet including bevacizumab, etc.)
2. Neoadjuvant and adjuvant systemic therapy will be counted as one line of therapy
3. Patients must have received at least one platinum-based therapy

   6. Patients must have progression disease after last therapy and have measurable disease according to RECIST (v1.1).

   7. Patients must have an ECOG performance status of 0 or 1. 8. Patients must have adequate organ function, defined as follows:

Hematological:

1. Absolute neutrophil count (ANC) ≥ 1,500/μL (without granulocyte-colony stimulating factor (G-CSF))
2. Platelets ≥ 100,000/μL (without transfusion)
3. Hemoglobin ≥ 9.0 g/dL (without transfusion)

Renal:

a. Serum Creatinine OR estimated glomerular filtration rate using the Cockcroft-Gault equation ≤ 1.5 × the upper limit of normal (ULN) OR 40 mL/min using the Cockcroft-Gault equation for patients with creatinine levels \> 1.5 × ULN

Hepatic:

1. Serum total bilirubin ≤ 1.5 ULN
2. Aspartate aminotransferase (AST) and alanine transaminase (ALT) ≤ 2.5 × ULN OR ≤ 5 × ULN for patients with liver metastases

Cardiac:

1. Multigated acquisition (MUGA) scan or echocardiogram with left ventricular ejection fraction (LVEF) ≥ 40%.
2. QTcF (QT corrected based on Fridericia's equation) interval \< 480 msec

Coagulation:

1. International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 × ULN
2. Activated Partial Thromboplastin Time (aPTT) or Partial Thromboplastin Time (PTT) ≤ 1.5 × ULN

   9. Patients must provide a fresh tissue biopsy, if medically feasible, or archival tissue as either a formalin-fixed and paraffin embedded FFPE) block or newly sectioned tissue on charged slides (equivalent to approximately 8-23 slides sectioned at 4-5μm thickness) 10. Patients of childbearing potential must have a negative serum or urine pregnancy test at screening 11. Patients must be either postmenopausal, free from menses \> 12 months, surgically sterilized, or willing to use adequate contraception to prevent pregnancy or must agree to abstain from heterosexual activity throughout the study, starting with enrollment through 6 months after the last dose of study treatment 12. Life expectancy ≥ 3 months 13. Patients who had stayed on the last treatment for at least 12 weeks without any evidence of progression

Exclusion Criteria Phase 2:

Patients with any of the following will be excluded from the study:

1. Primary platinum refractory patients defined as patients who experienced disease progression during the treatment with first-line platinum therapy
2. Patients with a known, untreated brain metastasis. Patients with treated brain metastases must be clinically stable for 4 weeks after completion of treatment for brain metastases and have radiographic image documentation of stability. Patients must have no clinical symptoms from brain metastases and not have required systemic corticosteroids \> 10 mg/day prednisone or equivalent for at least 4 weeks prior to the first dose
3. Patients who have received prior treatment with any other anti-PD-1, or PD-L1 or PD-L2 agent or an antibody or a small molecule targeting other immuno-regulatory receptors or mechanisms (examples of such drugs include but are not limited to antibodies against CTLA-4, LAG-3, IDO, PD-L1, IL-2R, GITR)
4. Patients who have received prior treatment with any other Wilms Tumor 1 (WT1)-related agents including peptide vaccine, dendric cell vaccine, and gene therapy
5. Patients who have received treatment for ovarian cancer within the following time frame prior to the first dose of the study

   1. Cytotoxic chemotherapy, hormonal therapy; ≤ 3 weeks
   2. Targeted therapy except for monoclonal antibody; ≤ 3 weeks
   3. Immune therapy, biologic therapy (e.g. antibodies); ≤ 4 weeks
   4. Other investigational agents: ≤ 4 weeks
   5. Radiation therapy (except for localized radiotherapy for analgesic purpose) ≤ 4 weeks
   6. Radiation therapy (localized radiotherapy for analgesic purpose) ≤ 1 week
   7. Major surgery regardless of reason ≤ 4 weeks.
6. Patients who have received a live vaccine within 4 weeks prior to the first dose.
7. Any known additional malignancy that is progressing or requires active treatment with the exception of:

   1. curatively treated basal cell or squamous cell carcinoma of skin
   2. curatively treated superficial bladder cancer, carcinoma in situ of the cervix,
   3. any another cancer from which the patient has been disease free for ≥ 3 years without any active treatment that, in the opinion of the Investigator and medical monitor for the Sponsor, will not affect patient's outcome in the setting of the current diagnosis.
8. Patients who have not recovered to \< CTCAE Grade 2 or baseline from toxic effect (with exception of alopecia and/or neuropathy) of prior cancer therapy.
9. Patients who have an active autoimmune disease requiring systemic immunosuppression in excess of physiologic maintenance dose of corticosteroids (\> 10 mg/day prednisone or equivalent) or any other forms of immunosuppressive therapy within 7 days prior to the first dose of study drug.
10. Positive serology for HIV infection, active hepatitis B, or hepatitis C
11. Patients who have a known history of bacillus tuberculosis (TB).
12. Patients with impaired cardiac function or clinically significant cardiac disease;

    * New York Hospital Association Class III or IV cardiac disease, including preexisting clinically significant ventricular arrythmia, congestive heart failure, or cardiomyopathy
    * Unstable angina pectoris ≤ 6 months before study participation
    * Myocardial infarction or stroke ≤ 6 months before study participation
13. Patients who have an interstitial lung disease or a history of pneumonitis that required oral or intravenous glucocorticoids to assist with management
14. Patients with active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy
15. Patients with any psychiatric condition, substance abuse disorder, or social situation that would interfere with a patient's cooperation with the study requirements and schedule
16. Patients with any condition that would, in the investigator's judgment, interfere with full participation including administration of study drugs, attending required visits or interfere with interpretation of study data
17. Patients who are pregnant or breastfeeding
18. Patients who have known hypersensitivity to DSP-7888 Dosing Emulsion, pembrolizumab, their components, or their excipients
19. Patient has dyspnea at rest (CTCAE ≥ Grade 3) or has required supplemental oxygen within 2 weeks of study enrollment
20. Patients with history of bowel obstruction related to underlying disease within 3 months prior to the first dose of study treatment