A Study of DSP-7888 Dosing Emulsion in Combination With Immune Checkpoint Inhibitors in Adult Patients With Advanced Solid Tumors
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 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. Once the recommended dose is 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. Approximately
 80 patients in total will be enrolled in the study, if both groups in Phase 2 are enriched
 with an additional 20 patients. This brings the total maximum study population to
 approximately 104 patients. Patients in the enrichment cohort will not be replaced.
Inclusion Criteria Phase 1b:

 Patients must fulfill each of the following requirements:

 1. 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

 -  Note: Only patients with locally advanced or metastatic RCC or urothelial
 carcinoma are eligible for participation in the Phase 1b enrichment cohort.

 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.

 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. This exclusion is not applicable to patients who meet the inclusion
 criterion #1b (ii).

 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
 infection, clinically significant non-healing or healing wounds, symptomatic
 congestive heart failure, unstable angina pectoris, severe and/or uncontrolled cardiac
 arrhythmia, significant pulmonary disease, uncontrolled infection 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. (Patients with bundle branch block and a prolonged QTc
 interval should be reviewed by the Medical Monitor for potential inclusion.)

 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.

 Note: Patients who have completed a course of antiviral treatment for hepatitis C and
 are cured are eligible. In cases of negative results, hepatitis B surface antigen with
 positive hepatitis B core antibody, and hepatitis B virus DNA testing are required.

 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):

 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. Patients must have histologically diagnosed serous epithelial 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 or adjuvant systemic therapy counts as one line of therapy
 respectively

 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 150 days after the last dose of study treatment.

 12. Life expectancy ≥ 3 months.

 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) 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

 • In cases of negative results for HepB surface antigen with positive HepB core
 antibody, hepatitis B virus (HBV) DNA greater than the lower limits of detection is
 not acceptable.

 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 infections that have required treatment with systemic antibiotics within
 7 days prior to the first dose of protocol 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.