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

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 1b/2, Multicenter, Open-Label Study of DSP-7888 Dosing Emulsion in Combination With Immune Checkpoint Inhibitors Nivolumab or Pembrolizumab in Adult Patients With Advanced Solid Tumors

Conditions
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Renal Cell Carcinoma (RCC), Urothelial Carcinoma, Primary Peritoneal Cancer, Platinum-resistant Ovarian Cancer (PROC), Serous Epithelial Ovarian Cancer, Fallopian Tube Cancer

Intervention / Treatment
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* Drug: DSP-7888 Dosing Emulsion
* Drug: Nivolumab
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Phase 1b: Patients must fulfill each of the following requirements: 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: Patients must not be considered eligible for a potentially curative resection. 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 Patients must be positive for at least 1 of the following human leukocyte antigens: HLA-A*02:01 HLA-A*02:06 HLA-A*24:02 HLA-A*03:01 HLA-B*15:01 ≥ 18 years of age Eastern Cooperative Oncology group (ECOG) performance status of 0 or 1 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 Females of childbearing potential must have a negative serum pregnancy test 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 Total bilirubin of ≤ 2.0 mg/dL (≤ 3.0 mg/dL for patients with known Gilbert's syndrome) Aspartate aminotransferase (AST) ≤ 3.0 × the upper limit of normal (ULN) or < 5 × ULN if considered to be due to liver metastases Alanine transaminase (ALT) ≤ 3.0 × the upper limit of normal (ULN) or < 5 × ULN if considered to be due to liver metastases Glomerular Filtration Rate > 40 mL/min Multigated acquisition (MUGA) scan or echocardiogram with left ventricular ejection fraction (LVEF) > 40% Life expectancy ≥ 3 months 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: Anticancer chemotherapy (including molecular targeted drugs), immunotherapy, radiotherapy, or investigational agents within 4 weeks of the first dose of DSP 7888 Dosing Emulsion Major surgery within 4 weeks prior to study treatment Patients who have received a live vaccine within 4 weeks prior to the first dose 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 Patients who have multifocal glioblastoma Pregnant or breastfeeding 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 Patients who have interstitial lung disease or active, non-infectious pneumonitis Known hypersensitivity to a component of protocol therapy: Patients with known hypersensitivity to any of the components of DSP-7888 Dosing Emulsion. Patients with known hypersensitivity to nivolumab or pembrolizumab are excluded from receiving combination therapy that includes the agent to which they are hypersensitive 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 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 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 who have a medical history of frequent or sustained ventricular ectopy 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 Known history of human immunodeficiency virus (HIV) infection, active hepatitis B, or untreated hepatitis C 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; 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.) Neoadjuvant and adjuvant systemic therapy will be counted as one line of therapy 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: Absolute neutrophil count (ANC) ≥ 1,500/μL (without granulocyte-colony stimulating factor (G-CSF)) Platelets ≥ 100,000/μL (without transfusion) 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: Serum total bilirubin ≤ 1.5 ULN Aspartate aminotransferase (AST) and alanine transaminase (ALT) ≤ 2.5 × ULN OR ≤ 5 × ULN for patients with liver metastases Cardiac: Multigated acquisition (MUGA) scan or echocardiogram with left ventricular ejection fraction (LVEF) ≥ 40%. QTcF (QT corrected based on Fridericia's equation) interval < 480 msec Coagulation: International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 × ULN 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: Primary platinum refractory patients defined as patients who experienced disease progression during the treatment with first-line platinum therapy 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 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) Patients who have received prior treatment with any other Wilms Tumor 1 (WT1)-related agents including peptide vaccine, dendric cell vaccine, and gene therapy Patients who have received treatment for ovarian cancer within the following time frame prior to the first dose of the study Cytotoxic chemotherapy, hormonal therapy; ≤ 3 weeks Targeted therapy except for monoclonal antibody; ≤ 3 weeks Immune therapy, biologic therapy (e.g. antibodies); ≤ 4 weeks Other investigational agents: ≤ 4 weeks Radiation therapy (except for localized radiotherapy for analgesic purpose) ≤ 4 weeks Radiation therapy (localized radiotherapy for analgesic purpose) ≤ 1 week Major surgery regardless of reason ≤ 4 weeks. Patients who have received a live vaccine within 4 weeks prior to the first dose. Any known additional malignancy that is progressing or requires active treatment with the exception of: curatively treated basal cell or squamous cell carcinoma of skin curatively treated superficial bladder cancer, carcinoma in situ of the cervix, 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. 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. 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. Positive serology for HIV infection, active hepatitis B, or hepatitis C Patients who have a known history of bacillus tuberculosis (TB). 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 Patients who have an interstitial lung disease or a history of pneumonitis that required oral or intravenous glucocorticoids to assist with management Patients with active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy 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 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 Patients who are pregnant or breastfeeding Patients who have known hypersensitivity to DSP-7888 Dosing Emulsion, pembrolizumab, their components, or their excipients Patient has dyspnea at rest (CTCAE ≥ Grade 3) or has required supplemental oxygen within 2 weeks of study enrollment Patients with history of bowel obstruction related to underlying disease within 3 months prior to the first dose of study treatment

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DSP-7888 Dosing Emulsion in combination with Nivolumab<br> | Drug: DSP-7888 Dosing Emulsion<br>* DSP-7888 Dosing Emulsion will be administered intradermally (ID) every 7 days until cycle 3, and then every 14 days for combination with Nivolumab arm or every 21 days for combination with Pembrolizumab arm.<br>* Other names: Ombipepimut-S (adegramotide and nelatimotide);Drug: Nivolumab<br>* Nivolumab will be administered in the approved dose and schedule starting on Day 29 of the study.<br>* Other names: Opdivo;|
| Experimental: DSP-7888 Dosing Emulsion in combination with Pembrolizumab<br> | Drug: DSP-7888 Dosing Emulsion<br>* DSP-7888 Dosing Emulsion will be administered intradermally (ID) every 7 days until cycle 3, and then every 14 days for combination with Nivolumab arm or every 21 days for combination with Pembrolizumab arm.<br>* Other names: Ombipepimut-S (adegramotide and nelatimotide);Drug: Pembrolizumab<br>* Pembrolizumab will be administered in the approved dose and schedule starting on Day 22 of the study.<br>* Other names: Keytruda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase Ib: Determination of the safety and tolerability of DSP-7888 Dosing Emulsion given intradermally with a checkpoint inhibitor (Nivolumab or Pembrolizumab) in adult patients with advanced solid tumors by assessing dose-limiting toxicities (DLTs). |  | 6 weeks | 
| Phase Ib: Determination of the Recommended Phase 2 Dose (RP2D) by assessing dose-limiting toxicities (DLTs). |  | 6 weeks | 
| Phase II: Evaluation of the preliminary antitumor activity of DSP-7888 Dosing Emulsion administered with pembrolizumab in terms of Objective Response Rate (ORR) in patients with platinum-resistant ovarian cancer (PROC). | Defined as the proportion of patients who have achieved confirmed CR or PR by RECIST v1.1 based on investigator assessment. | Up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase Ib: Objective response rate (ORR) | Defined as the proportion of patients who have achieved confirmed complete response (CR) or partial response (PR) evaluated using RECIST v1.1 and iRECIST. | 12 months | 
| Phase Ib: Disease control rate (DCR) | Defined as the percentage of patients who have achieved best overall response (BOR) of complete response (CR), partial response (PR), or stable disease (SD) per RECIST v1.1 and iRECIST. | 6 months | 
| Phase Ib: Duration of response (DOR) | Defined as the time from first documentation of response until the time of first documentation of disease progression by RECIST v1.1 and iRECIST or death by any cause. | 6 months | 
| Phase Ib: Progression-free survival (PFS) | Defined as the time from first dose of study treatment to the earlier date of assessment of progression by RECIST v1.1 and iRECIST or death by any cause. | 12 months | 
| Phase Ib: 6-month PFS | Defined as the proportion of patients who neither progressed by RECIST v1.1 and iRECIST nor died before six months (24 weeks) from the first study treatment. | 6 months | 
| Phase Ib: Overall survival (OS) | Defined as the time from the date of first dose of study treatment to the date of death by any cause. | 12 months | 
| Phase II: DOR | Defined as the time from the first documentation of a response (CR or PR) until time of first documentation of disease progression by RECIST v1.1 or death by any cause. | Up to 24 months | 
| Phase II: DCR | Defined as the percentage of patients who have achieved BOR of CR, PR, or SD per RECIST v1.1. | Up to 24 months | 
| Phase II: PFS | Defined as the time from the date of the first dose of study treatment to the earlier date of assessment of progression by RECIST v1.1 or death by any cause. | Up to 24 months | 
| Phase II: 6-month PFS | Defined as the proportion of patients who neither progressed by RECIST v1.1 nor died before 6 months (24 weeks) from the first study treatment. | 6 months | 
| Phase II: OS | Defined as the time from the date of first dose of study treatment to the date of death by any cause. | Up to 48 months | 
| Phase II: Immune objective response rate (iORR) | Defined as the proportion of patients who have achieved confirmed immune complete response (iCR) or immune partial response (iPR), evaluated using iRECIST based on investigator assessment. | Up to 24 months | 
| Phase II: Immune disease control rate (iDCR) | Defined as the percentage of patients who have achieved BOR of iCR, iPR, or iSD per iRECIST. | Up to 24 months | 
| Phase II: Immune progression-free survival (iPFS) | Defined as the time from the date of the first dose of study treatment to the earlier date of assessment of progression by iRECIST or death by any cause. | Up to 24 months | 
| Phase II: immune DOR (iDOR) | Defined as the time from the first documentation of response (iCR or iPR) until time of first documentation of disease progression by iRECIST, or death by any cause | Up to 24 months | 
| Phase II: Evaluation of the safety and tolerability of DSP-7888 Dosing Emulsion administered with pembrolizumab. | Determined by frequency and intensity of adverse events (AE) using Common Terminology Criteria for Adverse Events (CTCAE) ver 4.03. | Up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DSP-7888, Nelatimotide, Adegramotide, immune checkpoint inhibitor, cancer vaccine, WT1, ICI, Wilms Tumor 1, Ombipepimut-S, nivolumab, Opdivo, pembrolizumab, Keytruda, Ovarian cancer, Platinum-resistant ovarian cancer, PROC, Serous epithelial ovarian cancer, High-grade serous epithelial ovarian cancer, HGSOC, Fallopian tube cancer, FTC, Peritoneal cancer, Primary peritoneal cancer, PPC, Renal cell carcinoma, Kidney cancer, RCC, Metastatic Renal Cell Carcinoma, Metastatic RCC, Metastatic kidney cancer, Advanced Renal Cell Carcinoma, Advanced RCC, Advanced kidney cancer, Urothelial carcinoma, Bladder cancer, Transitional cell carcinoma, UC, Metastatic urothelial carcinoma, Metastatic transitional cell carcinoma, Metastatic UC, Advanced urothelial carcinoma, Advanced UC, Advanced transitional cell carcinoma