Naptumomab Estafenatox in Combination with Durvalumab in Subjects with Selected Advanced or Metastatic Solid Tumor, Including a Cohort Expansion in Esophageal Cancer.

Study Purpose

This Phase 1b is a dose escalation, MTD expansion and cohort expansions study to assess the safety and tolerability of a combination of NAP with durvalumab in subjects with selected advanced or metastatic solid tumors.

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	18 Years and Over
Gender	All

More Inclusion & Exclusion Criteria

Subjects must meet all of the following criteria to participate in this study: 1. Adult at least 18 years of age. 2. For the Dose-escalation and MTD Expansion Cohorts: Histologically and/or cytologically confirmed solid tumor from the following list, that is metastatic/advanced, and for which no curative therapy exists: 1. Pancreatic adenocarcinoma. 2. High-grade serous ovarian cancer. 3. Cervical squamous cell carcinoma. 4. Prostate cancer. 5. ER+/HER2- or triple-negative breast cancer. 6. NSCLC including driver mutation positive. 7. Mesothelioma. 8. Renal cell carcinoma. 9. Bladder/urothelial cancer. 10. Head and neck squamous cell carcinoma. 11. Melanoma. 12. Hepatocellular carcinoma. 13. Endometrial cancer. 14. MTD Expansion Cohort only: 5T4-positive colorectal cancer and 5T4 positive GE cancer. 3. For the Esophageal Expansion Cohort: Subjects must have histologically confirmed locally advanced or metastatic ESCC or AC of the esophagus or GEJ (Siewert type 1). 4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 5. All patients must provide signed informed consent prior to any study specific procedures that are not part of standard medical care. 6. In the MTD Expansion Cohort only, an archival or fresh biopsy will be acceptable at baseline. A second biopsy on Cycle 2 Day 4 is optional for patients who provided a fresh biopsy at baseline or have a tumor sample available from up to 3 months prior to study entry. Patients enrolled in the MTD expansion cohort after prior exposure to a CPI should have a baseline biopsy obtained after completion of the last prior CPI therapy. For the Esophageal Cohort Expansion: Subjects must have adequate tumor tissue (as defined in the laboratory manual) for biomarker analysis. If the archival tissue was taken > 1 year prior to screening into the trial, a fresh biopsy is required. Patients enrolled in Group 2 should have a baseline biopsy obtained after completion of the last prior CPI therapy. Bone samples, fine needle aspirates, brushings, cell pellets, and lavage are not acceptable samples. 7. Presence of clinically and/or radiologically documented disease. All radiology studies must be performed within 28 days prior to Cycle 1 Day 1 (first NAP treatment day) 1. Dose-escalation part: patients do not need to have measurable disease by RECIST 1.1. 2. MTD Dose Expansion: patients must have measurable disease by iRECIST/RECIST 1.1. Previously irradiated lesions may be considered measurable if there has been demonstrated progression in these lesions. 3. For the Esophageal Cohort Expansion: Patients must have measurable disease per iRECIST/RECIST version 1.1 by local investigator/ radiology assessment, unresectable based on documented opinion, or refusing surgery. 8. Previous therapy: a. Dose Escalation and MTD Expansion: i. All patients must have received at least 1 standard systemic cancer therapy for their tumor type and progressed following their most recent regimen. There is no limit to the number of prior cytotoxic regimens received. ii. Treatment-naïve patients will be eligible only if they refused standard treatment. iii. Patients with prior anti-PD-1, anti PD-L1, or anti-CTLA4 therapy are eligible if they have received such therapy for a minimum of 6 months and if they have documented progression of their disease on or off such therapy. b. Esophageal Cohort Expansion: i. Group 1

- no prior CPI: Subjects with only ESCC who may have received up to 1 prior chemotherapy as a line for metastatic disease or up to 2 prior chemotherapies if they also received neoadjuvant/adjuvant systemic therapy, but no prior CPI.

If subjects received prior chemotherapy for metastatic disease, they should have documented radiographic or clinical progression. ii. Group 2

- prior CPI: Subjects with either ESCC or AC of the esophagus or GEJ (Siewert type 1) who must not have had more than 2 prior lines of therapy.

Patients will be allowed to have up to 2 prior regimens for metastatic disease, or up to 3 prior therapies if they also received neoadjuvant/adjuvant systemic therapy. Subjects are eligible provided that they have received CPI therapy for at least 9 weeks, provided that they have documented progression of their disease on such therapy, and provided that the prior CPI was not discontinued for toxicity. No more than 1 prior CPI treatment is allowed (prior combination of anti-PD-[L]1 and anti-CTLA-4 is acceptable). Subjects with AC that is HER 2/neu negative. 9. Subjects with known, suspected, or documented parenchymal brain metastases, unless treated with surgery and/or radiation, with the subject neurologically stable and off pharmacologic doses of systemic glucocorticoids (equivalent to < 10 mg/day of prednisone); subjects with leptomeningeal metastases are not eligible. Subjects should have completed brain radiation at least 14 days before start of obinutuzumab treatment. 10. Prior treatment with chemotherapy or other systemic antineoplastic therapy within 21 days; prior experimental therapy within 21 days or 5 half-lives, whichever is shorter. 11. The use of immunosuppressive agents within 28 days of obinutuzumab administration including, but not limited to, cyclosporine, mycophenolate, azathioprine, methotrexate, adalimumab, infliximab, vedolizumab, tofacitinib, dupilumab, rituximab, etc. Pharmacologic doses of glucocorticoids defined as glucocorticoid equivalents of > 10 mg/day of prednisone (except when required for study medications or used prior to administration of radiographic contrast material in subjects with allergies) are not acceptable within 14 days of obinutuzumab administration. Subjects are permitted to receive topical, intranasal, inhalational, and intra ocular glucocorticoids. 12. Adequate hematologic and organ function: 1. White blood cells (WBC) ≥ 3000/μL. 2. Absolute neutrophil count (ANC) ≥ 1500/μL. 3. Platelets ≥ 100,000/μL. 4. Hemoglobin ≥ 9 g/dL. 5. Serum creatinine ≤ 1.5 mg/dL or calculated creatinine clearance (CrCL) > 40 mL/sec by Cockcroft-Gault (using actual body weight) 6. Aspartate aminotransferase (AST) ≤ 2.5 × upper limit of normal (ULN); alanine aminotransferase (ALT) ≤ 2.5 × ULN (for patients with known liver involvement AST and ALT ≤ 5 × ULN); bilirubin ≤ 1.5 mg/dL (unless diagnosed with Gilbert's syndrome) 7. International normalized ratio (INR) or prothrombin time (PT) and activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN. Subjects on anticoagulant therapy should be discussed with the Medical Monitor. 13. Patients must be willing and able to comply with scheduled visits, drug administration plan, hospitalization for treatment (if needed) and scheduled follow-up visits and examinations as outlined in the protocol, including procedures undertaken to perform fresh tumor biopsies if needed. 14. Must have a life expectancy of at least 3 months. 15. Negative pregnancy test (serum) for women of childbearing potential. 16. Female participants must be ≥ 1 year post-menopausal, surgically sterile, or using 1 highly effective form of birth control (a highly effective method of contraception is defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly.) Women of childbearing potential must agree to use 1 highly effective method of birth control. They should have been stable on their chosen method of birth control for a minimum of 3 months before entering the study until 90 days after the last dose of NAP + durvalumab combination therapy or durvalumab monotherapy. Non sterilized male partners of a female subject of childbearing potential must use a male condom plus spermicide throughout this period. 17. Male participants who intend to be sexually active with a female partner of childbearing potential must be surgically sterile or using an acceptable method of contraception from the time of Screening throughout the total duration of the study and until 90 days after the last dose of NAP + durvalumab combination therapy or durvalumab monotherapy to prevent pregnancy in a partner. Male participants must not donate or bank sperm during this same time period.

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT03983954
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	Phase 1
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	NeoTX Therapeutics Ltd.
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	Tal Hetzroni Kedem
Principal Investigator Affiliation	NeoTX Therapeutics Ltd.
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Industry
Overall Status	Recruiting
Countries	India, Israel
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	ER+ Breast Cancer, Ovarian Cancer, Cervical Squamous Cell Carcinoma, Pancreatic Adenocarcinoma, Endometrial Cancer, Renal Cell Carcinoma, Urothelial Cancer, Head and Neck Squamous Cell Carcinoma, Mesothelioma, Melanoma, Hepatocellular Carcinoma, Prostate Cancer, NSCLC, HER2-negative Breast Cancer, Triple Negative Breast Cancer, Bladder Cancer, Colorectal Cancer Metastatic, GastroEsophageal Cancer, NSCL2 Gene Mutation, Esophageal Cancer

Additional Details

This Phase 1b study was originally designed for patients with tumors reported to have a high probability of expressing the 5T4 antigen. An amended protocol extended the eligibility criteria of patients recruited to the maximum tolerated dose (MTD) cohort, to include colorectal cancer (CRC) and GE carcinomas. Following the Dose Escalation part, antibodies binding to NAP have been shown to interfere with drug exposure, which makes it unlikely that patients could effectively receive more than 3 cycles of NAP. Obinutuzumab pretreatment was added to the combination of durvalumab and NAP given at the 2 highest safe dose levels of the combination of durvalumab and NAP in the dose-escalation part of this Phase 1b study (3 patients per dose level), and to the MTD expansion part that included several cohorts. The combination of NAP/durvalumab combination will be further evaluated at the Recommended Phase 2 Dose (RP2D) established in the dose- escalation part, (10 µg/kg/dose), in an expansion cohort of subjects with advanced/metastatic carcinoma of the esophagus.

Arms & Interventions

Arms

Experimental: Dose Escalation naptumomab estafenatox 2 µg/kg and durvalumab

NAP was administered on the first four days of each 21-day cycle, at daily doses of 2 µg/kg. Durvalumab (1120 mg, IV, 1- 1.5 hours after completion of the administration of NAP) was administered on the second day of each 21-day cycle. After cycle 3, patients continued to receive durvalumab alone at a dose of 1500 mg delivered once every 28 days, until confirmed disease progression or unacceptable toxicity for a maximum of up to 24 months.

Experimental: Dose Escalation naptumomab estafenatox 5 µg/kg and durvalumab

NAP was administered on the first four days of each 21-day cycle, at daily doses of 5 µg/kg. Durvalumab (1120 mg, IV, 1- 1.5 hours after completion of the administration of NAP) was administered on the second day of each 21-day cycle. After cycle 3, patients continued to receive durvalumab alone at a dose of 1500 mg delivered once every 28 days, until confirmed disease progression or unacceptable toxicity for a maximum of up to 24 months.

Experimental: Dose Escalation naptumomab estafenatox 10 µg/kg and durvalumab

NAP was administered on the first four days of each 21-day cycle, at daily doses of 10 µg/kg. Durvalumab (1120 mg, IV, 1- 1.5 hours after completion of the administration of NAP) was administered on the second day of each 21-day cycle. After cycle 3, patients continued to receive durvalumab alone at a dose of 1500 mg delivered once every 28 days, until confirmed disease progression or unacceptable toxicity for a maximum of up to 24 months.

Experimental: Dose Escalation naptumomab estafenatox 15 µg/kg and durvalumab

NAP was administered on the first four days of each 21-day cycle, at daily doses of 15 µg/kg. Durvalumab (1120 mg, IV, 1- 1.5 hours after completion of the administration of NAP) was administered on the second day of each 21-day cycle. After cycle 3, patients continued to receive durvalumab alone at a dose of 1500 mg delivered once every 28 days, until confirmed disease progression or unacceptable toxicity for a maximum of up to 24 months.

Experimental: Dose Escalation naptumomab estafenatox 20 µg/kg and durvalumab

NAP was administered on the first four days of each 21-day cycle, at daily doses of 20 µg/kg. Durvalumab (1120 mg, IV, 1- 1.5 hours after completion of the administration of NAP) was administered on the second day of each 21-day cycle. After cycle 3, patients continued to receive durvalumab alone at a dose of 1500 mg delivered once every 28 days, until confirmed disease progression or unacceptable toxicity for a maximum of up to 24 months.

Experimental: Dose escalation, obinutuzumab pretreatment followed by NAP 10 µg/kg and durvalumab

Obinutuzumab (1000 mg/day) was administered on days 13 and 12 prior to the first day of NAP. NAP was administered on the first four days of each 21-day cycle, at daily doses of 10 µg/kg. Durvalumab (1120 mg, IV, 1- 1.5 hours after completion of the administration of NAP) was administered on the second day of each 21-day cycle. After cycle 3, patients continued to receive durvalumab alone at a dose of 1500 mg delivered once every 28 days, until confirmed disease progression or unacceptable toxicity for a maximum of up to 24 months.

Experimental: Dose escalation, obinutuzumab pretreatment followed by NAP 15 µg/kg and durvalumab

Obinutuzumab (1000 mg/day) was administered on days 13 and 12 prior to the first day of NAP. NAP was administered on the first four days of each 21-day cycle, at daily doses of 15 µg/kg. Durvalumab (1120 mg, IV, 1- 1.5 hours after completion of the administration of NAP) was administered on the second day of each 21-day cycle. After cycle 3, patients continued to receive durvalumab alone at a dose of 1500 mg delivered once every 28 days, until confirmed disease progression or unacceptable toxicity for a maximum of up to 24 months.

Experimental: MTD expansion, obinutuzumab pretreatment with NAP at MTD and durvalumab

NAP at 15mcg/kg and durvalumab (1120 mg) were given for 6 cycles after pre-treatment of obinutuzumab (1000 mg/day) on D-13 and D-12. After cycle 6, patients continued to receive durvalumab alone at a dose of 1500 mg delivered once every 28 days, until confirmed disease progression or unacceptable toxicity for a maximum of up to 24 months.

Experimental: MTD expansion, obinutuzumab pretreatment with NAP, at the previous dose level, and durvalumab

NAP, at the previous dose level (10mcg/kg), and durvalumab (1120 mg) were given for 6 cycles after pre-treatment of obinutuzumab (1000 mg/day) on D-13 and D-12. After cycle 6, patients continued to receive durvalumab alone at a dose of 1500 mg delivered once every 28 days, until confirmed disease progression or unacceptable toxicity for a maximum of up to 24 months.

Experimental: MTD expansion, abbreviated regimen of obinutuzumab pretreatment with NAP at MTD and durvalumab

NAP at MTD (10 mcg/kg/day) and durvalumab (1120 mg) were given for 6 cycles after a single dose of pre-treatment of obinutuzumab (1000 mg/day) on D-7. After cycle 6, patients continued to receive durvalumab alone at a dose of 1500 mg delivered once every 28 days, until confirmed disease progression or unacceptable toxicity for a maximum of up to 24 months.

Experimental: Cohort Expansion in Esophageal Cancer: Obinutuzumab pretreatment, NAP and Durvalumab

NAP will be administered at a dose of 10 μg/kg/day by IV bolus on Days 1 through 4 of the first 6 treatment cycles, and durvalumab will be administered at a flat dose of 1120 mg on Day 2 of each of the first 6 treatment cycles. Starting Cycle 7, a single administration of NAP at the same dose and durvalumab at the dose of 1500 mg will be administered on the same day (Day 1) in 28-day treatment cycles. The first 6 treatment cycles will be 21 days in duration and, starting Cycle 7 onward, treatment cycles will be 28 days in duration. Study treatment will continue until disease progression, untoward toxicity, noncompliance, or for a maximum duration of 2 years.

Interventions

Combination Product: - Obinutuzumab, naptumomab estafenatox and durvalumab

Obinutuzumab is given intravenous (I.V.) 1,000 mg concentrate for solution for infusion, as pre-treatment. Dose escalation and MTD Expansion: NAP is given as an intravenous (I.V.) bolus injection at multiple doses. Durvalumab is given at a dose of 1120 mg, I.V, 1- 1.5 hours after completion of the administration of NAP on the second day of each 21-day cycle, and when administered as monotherapy at a dose of 1500 mg delivered once every 28 days. Esophageal cohort expansion: NAP is given as an intravenous (I.V.) bolus injection at multiple doses on cycles 1-6 and one dose per cycle starting cycle 7. Durvalumab is given at a dose of 1120 mg, I.V, 1- 1.5 hours after completion of the administration of NAP on the second day of each 21-day cycle during cycles 1-6, and at a dose of 1500 mg delivered once every 28 days starting cycle 7.

Combination Product: - Naptumomab estafenatox and durvalumab

NAP was given as an intravenous (I.V.) bolus injection at multiple doses. Durvalumab was given at a dose of 1120 mg, I.V, 1- 1.5 hours after completion of the administration of NAP on the second day of each 21-day cycle, and when administered as monotherapy at a dose of 1500 mg delivered once every 28 days.

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