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

NCT03983954 | Active Not Recruiting Phase 1 FDA Drug

• 1 other identifier: 127-CL-01 (NT-NAP-101)
• Study Type: interventional
• Target: 120
• Locations: 2 countries
• Sites: 9

Brief Summary

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.

Conditions

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

Keywords

Esophageal cancer; Squamous cell carcinoma of the esophagus; Adenocarcinoma of the esophagus

Outcome Measures

Primary Outcomes (4)

• Part A: Dose Escalation / MTD Expansion: The incidence and characteristics of adverse events, associated with ascending doses of NAP in combination with a set dose of durvalumab

  Number of participants with infusion reactions, Dose Limiting Toxicity (DLT) during the first cycle of treatment and/or, any adverse events graded as per NCI Common Toxicity Criteria (CTC).

  From day 1 up to 90 days following last dose of study drug

• Part A: Dose Escalation / MTD Expansion: The incidence and characteristics of adverse events, associated with ascending doses of NAP in combination with a set dose of durvalumab and following pretreatment with obinutuzumab.

  Number of participants with infusion reactions (e.g. fever, chills, hypotension, tachycardia etc.), occurrence of any Dose Limiting Toxicity (DLT) during the first cycle of treatment and/or , any clinically significant changes from baseline graded as per NCI Common Toxicity Criteria (CTC).

  From day -13 up to 90 days following last dose of study drug

• Part A: Dose Escalation / MTD Expansion: The RP2D either with or without obinutuzumab pretreatment

  based on the observed safety effects in the DE and MTD expansion cohorts.

  From day -13 up to 90 days following last dose of study drug

• Part B: Esophageal Cohort Expansion - ORR

  The ORR by immune therapy-based Response Evaluation Criteria in Solid Tumours (iRECIST) of the combination of NAP with durvalumab in subjects with advanced/metastatic: 1. ESCC without exposure to prior anti PD-1/PD-L1 therapy (Group 1), OR 2. Squamous cell carcinoma or AC of the esophagus or GEJ who have received prior anti PD-1/PD-L1 therapy (Group 2).

  24 month

Secondary Outcomes (8)

• Part A: Dose Escalation / MTD Expansion: Disease parameters: ORR, DOR, PFS, OS

  From date of initiation of treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 6 months post last patient in.

• Part A: Dose Escalation: Establish Recommended Phase 2 Dose (RP2D)

  From Day 1 up to end of cycle 3 of dose escalation cohort without obinutuzumab

• Part A: Dose Escalation / MTD Expansion: Assessment of anti-NAP antibody levels and human anti-murine antibody (HAMA) levels at the beginning of each treatment cycle.

  From start of treatment till end of cycle 3 in dose escalation and end of cycle 6 in MTD expansion (each cycle is 21 days).

• Part A: Dose Escalation / MTD Expansion: Assessment of NAP plasma levels at select time points

  From start of treatment till end of cycle 3 in dose escalation and end of cycle 6 in MTD expansion (each cycle is 21 days).

• Part B: Esophageal Cohort Expansion: ORR

  24 month

Study Arms (11)

Dose Escalation naptumomab estafenatox 2 µg/kg and durvalumab

EXPERIMENTAL

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.

Combination Product: Naptumomab estafenatox and durvalumab

Dose Escalation naptumomab estafenatox 5 µg/kg and durvalumab

EXPERIMENTAL

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.

Combination Product: Naptumomab estafenatox and durvalumab

Dose Escalation naptumomab estafenatox 10 µg/kg and durvalumab

EXPERIMENTAL

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.

Combination Product: Naptumomab estafenatox and durvalumab

Dose Escalation naptumomab estafenatox 15 µg/kg and durvalumab

EXPERIMENTAL

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.

Combination Product: Naptumomab estafenatox and durvalumab

Dose Escalation naptumomab estafenatox 20 µg/kg and durvalumab

EXPERIMENTAL

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.

Combination Product: Naptumomab estafenatox and durvalumab

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

EXPERIMENTAL

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.

Combination Product: Obinutuzumab, naptumomab estafenatox and durvalumab

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

EXPERIMENTAL

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.

Combination Product: Obinutuzumab, naptumomab estafenatox and durvalumab

MTD expansion, obinutuzumab pretreatment with NAP at MTD and durvalumab

EXPERIMENTAL

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.

Combination Product: Obinutuzumab, naptumomab estafenatox and durvalumab

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

EXPERIMENTAL

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.

Combination Product: Obinutuzumab, naptumomab estafenatox and durvalumab

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

EXPERIMENTAL

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.

Combination Product: Obinutuzumab, naptumomab estafenatox and durvalumab

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

EXPERIMENTAL

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.

Combination Product: Obinutuzumab, naptumomab estafenatox and durvalumab

Interventions

Obinutuzumab, naptumomab estafenatox and durvalumab COMBINATION_PRODUCT

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.

Also known as: (ABR-217620; NAP), (IMFINZI; MEDI4736), [Gazyva]

Cohort Expansion in Esophageal Cancer: Obinutuzumab pretreatment, NAP and Durvalumab; Dose escalation, obinutuzumab pretreatment followed by NAP 10 µg/kg and durvalumab; Dose escalation, obinutuzumab pretreatment followed by NAP 15 µg/kg and durvalumab; MTD expansion, abbreviated regimen of obinutuzumab pretreatment with NAP at MTD and durvalumab; MTD expansion, obinutuzumab pretreatment with NAP at MTD and durvalumab; MTD expansion, obinutuzumab pretreatment with NAP, at the previous dose level, and durvalumab

Naptumomab estafenatox and durvalumab COMBINATION_PRODUCT

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.

Also known as: (ABR-217620; NAP), (IMFINZI; MEDI4736)

Dose Escalation naptumomab estafenatox 10 µg/kg and durvalumab; Dose Escalation naptumomab estafenatox 15 µg/kg and durvalumab; Dose Escalation naptumomab estafenatox 2 µg/kg and durvalumab; Dose Escalation naptumomab estafenatox 20 µg/kg and durvalumab; Dose Escalation naptumomab estafenatox 5 µg/kg and durvalumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

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.

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• NeoTX Therapeutics Ltd.: lead
• AstraZeneca: collaborator

Study Sites (9)

Shalby Hospital

Ahmedabad, Gujarat, 380015, India

Location

National Cancer Institute

Jhajjar, Haryana, 124105124105, India

Location

All India Institute of Medical Sciences

New Delhi, New Delhi, 110029, India

Location

PMCH (Pacific Medical College & Hospital)

Udaipur, Rajasthan, 313001, India

Location

Basavatarakam Indo-American Cancer Hospital & Research Institute

Hyderabad, Telangana, 500034, India

Location

Rambam Medical Center

Haifa, 3109601, Israel

Location

Rabin Medical Center

Petah Tikva, Israel

Location

Sheba Medical Center

Ramat Gan, 52621, Israel

Location

Tel Aviv Sourasky Medical Center

Tel Aviv, 6423906, Israel

Location

MeSH Terms

Conditions

Ovarian Neoplasms; Endometrial Neoplasms; Carcinoma, Renal Cell; Squamous Cell Carcinoma of Head and Neck; Mesothelioma; Melanoma; Carcinoma, Hepatocellular; Prostatic Neoplasms; Triple Negative Breast Neoplasms; Urinary Bladder Neoplasms; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Adenocarcinoma Of Esophagus

Interventions

obinutuzumab; naptumomab estafenatox; durvalumab

Condition Hierarchy (Ancestors)

Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders; Uterine Neoplasms; Uterine Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Kidney Neoplasms; Urologic Neoplasms; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases; Carcinoma, Squamous Cell; Head and Neck Neoplasms; Adenoma; Neoplasms, Mesothelial; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Skin Diseases; Skin and Connective Tissue Diseases; Liver Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Liver Diseases; Genital Neoplasms, Male; Genital Diseases, Male; Prostatic Diseases; Breast Neoplasms; Breast Diseases; Urinary Bladder Diseases; Gastrointestinal Neoplasms; Esophageal Diseases; Gastrointestinal Diseases; Neoplasms, Squamous Cell

Study Officials

• Tal Hetzroni Kedem

  NeoTX Therapeutics Ltd.

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 27, 2019
• First Posted: June 12, 2019
• Study Start: October 10, 2019
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): March 1, 2027
• Last Updated: November 28, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will not share

Locations

IL (4); IN (5)