Naptumomab Estafenatox in Combination with Durvalumab in Subjects with Selected Advanced or Metastatic Solid Tumor, Including a Cohort Expansion in Esophageal Cancer.
- Conditions
- ER+ Breast CancerOvarian CancerCervical Squamous Cell CarcinomaPancreatic AdenocarcinomaEndometrial CancerRenal Cell CarcinomaUrothelial CancerHead and Neck Squamous Cell CarcinomaMesotheliomaMelanoma
- Registration Number
- NCT03983954
- Lead Sponsor
- NeoTX Therapeutics Ltd.
- 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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 120
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Primary Outcome Measures
Name Time Method 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 From day 1 up to 90 days following last dose of study drug 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).
Part A: Dose Escalation / MTD Expansion: The RP2D either with or without obinutuzumab pretreatment From day -13 up to 90 days following last dose of study drug based on the observed safety effects in the DE and MTD expansion cohorts.
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. From day -13 up to 90 days following last dose of study drug 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).
Part B: Esophageal Cohort Expansion - ORR 24 month 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).
- Secondary Outcome Measures
Name Time Method 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. Tumor assessment for ORR, DOR and PFS according to the iRECIST and conventional RECIST 1.1. OS will be based on death events.
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 RP2D will be determined based on the observed effects of the MTD.
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). Blood levels of ADAs and HAMA
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). Pharmacokinetic calculations will be based on individual subject NAP plasma concentrations over time
Part B: Esophageal Cohort Expansion: ORR 24 month 1. The ORR by RECIST version 1.1 criteria, of the combination of NAP with durvalumab in subjects who are CPI naïve (ESCC; Group 1) and in subjects previously treated with a CPI (ESCC, AC; Group 2).
Part B: Esophageal Cohort Expansion: OS, PFS, DOR, rate & duration of disease control 24 month 2. To assess the following efficacy parameters in each group:
1. OS, defined as time of enrolling on study (start of any study treatment) to death from whatever cause.
2. PFS (by iRECIST and RECIST 1.1.), defined as the time of enrolling on study (start of any study treatment) to disease progression or death from whatever cause.
3. DOR (by iRECIST and RECIST 1.1.) in subjects who achieve an objective response (CR or PR) defined as the time from first evidence of response to PD.
4. Rate and duration of disease control (by iRECIST and RECIST 1.1.) in patients with CR, PR, or SD.Part B: Esophageal Cohort Expansion: safety and tolerability 24 month 3. Assessment of the safety and tolerability of NAP/durvalumab combination:
1. Safety will be measured by the incidence of treatment emergent adverse events (TEAEs), changes from baseline in vital signs, findings on physical examinations, ECGs, blood chemistry, complete blood count (CBC), urine and thyroid function laboratory tests, and graded per NCI CTCAE.
2. Adverse events of special interest will include immune-based, tissue specific autoimmune conditions (e.g., colitis, pneumonitis).
3. Tolerability will be measured by dose interruptions, dose reductions (NAP) and discontinuations due to drug-related AEs.Part B: Esophageal Cohort Expansion: Assessment of NAP plasma levels at select time points and ADAs 24 month 4. Assessment of plasma levels of total NAP and ADAs (to be analyzed centrally at Labcorp).
Trial Locations
- Locations (9)
Shalby Hospital
🇮🇳Ahmedabad, Gujarat, India
National Cancer Institute
🇮🇳Jhajjar, Haryana, India
PMCH (Pacific Medical College & Hospital)
🇮🇳Udaipur, Rajasthan, India
Basavatarakam Indo-American Cancer Hospital & Research Institute
🇮🇳Hyderabad, Telangana, India
All India Institute of Medical Sciences
🇮🇳New Delhi, India
Rambam Medical Center
🇮🇱Haifa, Israel
Rabin Medical Center
🇮🇱Petah Tikva, Israel
Sheba Medical Center
🇮🇱Ramat Gan, Israel
Tel Aviv Sourasky Medical Center
🇮🇱Tel Aviv, Israel
Shalby Hospital🇮🇳Ahmedabad, Gujarat, IndiaViraj Lavingia, DrContact+91-9818549149drvirajlavingia@gmail.com