Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu

Naptumomab Estafenatox in Combination With Durvalumab in Subjects With Selected Advanced or Metastatic Solid Tumors

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03983954
Recruitment Status : Not yet recruiting
First Posted : June 12, 2019
Last Update Posted : June 20, 2019
Sponsor:
Collaborator:
AstraZeneca Pharmaceuticals PLC
Information provided by (Responsible Party):
NeoTX Therapeutics Ltd.

Tracking Information
First Submitted Date  ICMJE May 27, 2019
First Posted Date  ICMJE June 12, 2019
Last Update Posted Date June 20, 2019
Estimated Study Start Date  ICMJE August 1, 2019
Estimated Primary Completion Date November 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 11, 2019)
  • The incidence and characteristics of adverse events, associated with ascending doses of Nap in combination with a set dose of durvalumab [ Time Frame: From day 1 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).
  • Establish MTD [ Time Frame: At the end of cycle 1 (each cycle is 21 days) ]
    MTD is defined as the highest dose at which no more than 1 of 6 subjects in a given cohort has experienced a DLT.
  • Establish Recommended Phase 2 Dose (RP2D) [ Time Frame: Day 1 up to end of cycle 3 of escalation cohort (each cycle is 21 days) ]
    RP2D will be determined based on the observed effects of the MTD.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03983954 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Naptumomab Estafenatox in Combination With Durvalumab in Subjects With Selected Advanced or Metastatic Solid Tumors
Official Title  ICMJE Phase 1B, Open-Label, Dose Escalation and Cohort Expansions Trial of Naptumomab Estafenatox (Nap, ABR-217620) in Combination With Durvalumab (MEDI4736) in Subjects With Selected Advanced or Metastatic Solid Tumors
Brief Summary This is a dose escalation (Phase 1b) and cohort expansions (Phase 2) 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, open-label, multicenter (n=3), prospective, dose-finding and MTD cohort expansion study, will accrue patients with previously treated solid tumors known with high likelihood of 5T4 antigen expression on tumor cells.

Patients in the dose-escalation part will be treated with the combination of Nap and durvalumab using a fixed dose of durvalumab and the 3+3 design for Nap dose escalations. The (Maximum Tolerated Dose (MTD) of Nap for the combination treatment will be established based on Dose Limiting Toxicities (DLTs) occurring during the first cycle of the treatment. The dose escalation part will be followed by a MTD expansion part, in which 10-15 patients will be treated with the same combination however using the established MTD of Nap. This MTD expansion cohort will accrue patients with the same tumor types as in the escalation part, but with a requirement of measurable disease. This expansion cohort will help assess the biologic activity of the combination and to gain some preliminary insights on its potential antitumor activity.

The following solid tumors known to have > 80% probability of 5T4 expression and thus may be included in both the dose escalation phase and the MTD expansion: breast cancer, epithelial ovarian cancer, cervical and endometrial cancer, pancreatic cancer, renal and urothelial cancer, head and neck, mesothelioma, melanoma, hepatic carcinoma, prostate cancer, and Non-Small Cell Lung Cancer (NSCLC). Prior PD-1 or PD-L1 therapy is acceptable.

Five dose levels of Nap are planned: 2, 5, 10, 15, and 20 µg/kg/dose given as an intravenous (I.V.) bolus injection daily on the first 4 consecutive days of the 21-day cycle, for a total of 3 treatment cycles (Days 1-4, 22-25, and 43-46). In parallel, durvalumab (1120 mg, IV, 1- 1.5 hours after completion of the administration of Nap) will be administered on the second day of each 21-day cycle. After cycle 3, patients will continue to receive durvalumab alone at a dose of 1500 mg delivered once every 28 days, until disease progression or unacceptable toxicity for a maximum of up to 24 months.Each subsequent cohort will only be opened after all patients in the preceding cohort completed the first cycle of treatment and <2 dose-limiting toxicities (DLTs) were reported.

MTD expansion cohort: In the MTD expansion cohort, treatment with the combination of Nap and durvalumab will be given for the first 3 treatment cycles at the same schedule described above but using the determined MTD of Nap and the same fixed dose of durvalumab. Additional treatment cycles with this combination beyond cycle 3 may be authorized by the Sponsor based on the pharmacokinetic findings in the dose escalation part of the study.

Patients in this cohort will be required to provide a fresh biopsy sample on Day 4 of Cycle 1, which will be assessed for tumor biomarkers and tumor gene microenvironment expression.

Follow-up:

  • Safety reporting will be collected for up to 90 days following administration of the last study dose, even in patients receiving subsequent anticancer therapy in the interval.
  • Tumor evaluations (CT/MRI) will be performed every 63 ± 7 days, regardless of treatment delays. Scans will be evaluated using the RECIST 1.1 and iRECIST guidelines.
  • Serologic and cellular immune biomarkers will be evaluated at the beginning and end of Cycles 1-3, as well as on Day 8 of Cycle 1.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

Nap dose-escalation cohorts will be run with a standard 3+3 design. A sentinel patient will be recruited at each dose level. Nap will be given for up to 3 cycles (dose escalation part) or more (MTD expansion part), depending on PK results, as described in this protocol.

Durvalumab will be administered at the following doses:

  • During cycles of combination with NAP: durvalumab will be administered at a set dose of 1120 mg, IV, on Day 2 of each 21-day cycle.
  • During cycles when it is delivered as a single agent: durvalumab will be administered at a set dose of 1500 mg, IV, on Day 1 of each 28-day cycle.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Breast Cancer
  • Epithelial Ovarian Cancer
  • Cervical Cancer
  • Pancreatic Cancer
  • Endometrial Cancer
  • Renal Cancer
  • Urothelial Cancer
  • Head and Neck Cancer
  • Mesothelioma
  • Melanoma
  • Hepatic Carcinoma
  • Prostate Cancer
  • NSCLC
Intervention  ICMJE Combination Product: Naptumomab estafenatox (ABR-217620; Nap) with durvalumab (IMFINZI; MEDI4736)
Nap is given as an intravenous (I.V.) bolus injection. Durvalumab is given 1120 mg, I.V, 1- 1.5 hours after completion of the administration of Nap
Study Arms  ICMJE
  • Experimental: Naptumomab estafenatox 2 µg/kg with durvalumab
    Nap is to be administered on the first four days of each 21-day cycle, at daily doses of 2 µg/kg according to the relevant assigned dose level.
    Intervention: Combination Product: Naptumomab estafenatox (ABR-217620; Nap) with durvalumab (IMFINZI; MEDI4736)
  • Experimental: Naptumomab estafenatox 5 µg/kg with durvalumab
    Nap is to be administered on the first four days of each 21-day cycle, at daily doses of 5 µg/kg according to the relevant assigned dose level.
    Intervention: Combination Product: Naptumomab estafenatox (ABR-217620; Nap) with durvalumab (IMFINZI; MEDI4736)
  • Experimental: Naptumomab estafenatox 10 µg/kg with durvalumab
    Nap is to be administered on the first four days of each 21-day cycle, at daily doses of 10 µg/kg according to the relevant assigned dose level.
    Intervention: Combination Product: Naptumomab estafenatox (ABR-217620; Nap) with durvalumab (IMFINZI; MEDI4736)
  • Experimental: Naptumomab estafenatox 15 µg/kg with durvalumab
    Nap is to be administered on the first four days of each 21-day cycle, at daily doses of 15 µg/kg according to the relevant assigned dose level.
    Intervention: Combination Product: Naptumomab estafenatox (ABR-217620; Nap) with durvalumab (IMFINZI; MEDI4736)
  • Experimental: Naptumomab estafenatox 20 µg/kg with durvalumab
    Nap is to be administered on the first four days of each 21-day cycle, at daily doses of 15 µg/kg according to the relevant assigned dose level.
    Intervention: Combination Product: Naptumomab estafenatox (ABR-217620; Nap) with durvalumab (IMFINZI; MEDI4736)
  • Experimental: Expansion pert: Naptumomab estafenatox MTD with durvalumab
    MTD Nap will be given for 3 cycles or more depending on PK results, as described in this protocol.
    Intervention: Combination Product: Naptumomab estafenatox (ABR-217620; Nap) with durvalumab (IMFINZI; MEDI4736)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: June 11, 2019)
45
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 28, 2022
Estimated Primary Completion Date November 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Histologically and/or cytologically confirmed solid tumor from the following list, that is metastatic/advanced, 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. driver mutation-positive NSCLC adenocarcinoma
    7. mesothelioma
    8. renal cell carcinoma
    9. bladder/ urothelial cancer
    10. head and neck carcinoma
    11. melanoma
    12. hepatocellular carcinoma
    13. endometrial cancer
  2. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
  3. a. All patients must provide signed informed consent prior to any study specific procedures that are not part of standard medical care.

    b. Patients in the MTD expansion cohort will also provide their consent to undergo 2 tumor biopsies: one prior to treatment (during screening) and the second on cycle 1 day 4. All efforts should be made to obtain 2 fresh biopsies for each patient. A prior formalin-fixed, paraffin-embedded tissue block or unstained slides from primary or metastatic tumor, taken not earlier than the time of diagnosis of metastatic disease, may be used as a substitute for the 1st fresh biopsy in patients with no prior immune-oncology (IO) therapy. Patients enrolled in the MTD expansion cohort after prior exposure to a checkpoint inhibitor should have a baseline biopsy obtained after completion of the last prior checkpoint inhibitor therapy.

  4. Presence of clinically and/or radiologically documented disease. All radiology studies must be performed within 28 days prior to subject enrolment (subject enrolment=Day 1)

    1. Dose escalation part: patients do not need to have measurable disease by RECIST 1.1
    2. MTD expansion part: patients must have measurable disease by RECIST 1.1 and at least one additional accessible lesion for biopsy. Previously irradiated lesions may be considered measurable if there has been demonstrated progression in these lesions.
  5. Previous therapy:

    1. Cytotoxic chemotherapy: There is no limit to the number of prior regimens received.
    2. Other Systemic Therapy:

    i.All patients must have received at least 1 standard systemic cancer therapy for their tumor type and progressed following their most recent regimen 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.

  6. Previously treated brain metastases must be asymptomatic without MRI evidence of progression for at least 8 weeks and off steroids for at least 4 weeks before study drug administration to be eligible.
  7. At least 21 days since the last chemotherapy, immunotherapy, biological (except for erythropoietin, denosumab and bisphosphonates), and at least 2 weeks from approved tyrosine kinase inhibitor therapy and recovery to grade 1 or less (except for alopecia) from any toxicity associated with such treatment.
  8. Systemic prednisone therapy ≤10 mg/day or equivalent is acceptable. Higher doses are not acceptable within 1 week prior to start of study treatment and as long as patient is treated with Nap. There is no limit on topical, intranasal or inhaled corticosteroids.
  9. Prior major surgery completed at least 4 weeks before study drug administration.
  10. Adequate hematologic and organ function: WBC (White Blood Cells) ≥3000/µL; neutrophils ≥1500/µL; platelets ≥100,000/µL; hemoglobin ≥10.0 g/dL (may have been transfused); creatinine ≤2 mg/dL; measured creatinine clearance >40 mL/min or calculated creatinine clearance (CL) > 40, as determined by Cockcroft-Gault (using actual body weight); AST (aspartate transaminase) ≤2.5 X ULN (Upper Limit of Normal); ALT ( alanine aminotransferase) ≤2.5 X ULN; bilirubin ≤ 1.5 mg/dL (unless diagnosed with Gilbert's syndrome); Coagulation International Normalized Ratio (INR) or Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants.
  11. 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 as per protocol
  12. Must have a life expectancy of at least 12 weeks

Exclusion Criteria:

  1. Body weight <30kg
  2. Patients with a history of other malignancies requiring concurrent anticancer therapy.
  3. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease (e.g. colitis or Crohn's disease), or other serious gastrointestinal chronic conditions associated with diarrhea), systemic lupus erythematosus, or Wegener syndrome (granulomatosis with polyangiitis), rheumatoid arthritis, uveitis, etc., within the past 2 years prior to the start of treatment. The following are exceptions to this criterion:

    1. Patients with alopecia
    2. Patients with Graves' disease, vitiligo or psoriasis not requiring systemic treatment (within the last 2 years).
    3. Patients with endocrinopathies (e.g. following Hashimoto syndrome) stable on hormone replacement or do not require any therapy.
  4. History of primary immunodeficiency, history of allogenic organ transplant that requires therapeutic immunosuppression and the use of immunosuppressive agents within 28 days of enrolment*.

    *NOTE: Intranasal/inhaled corticosteroids or systemic steroids that do not to exceed 10 mg/day of prednisone or equivalent dose of an alternative corticosteroid are permissible

  5. Patients who have uncontrolled inter-current illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, active interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs (Adverse Events) or compromise the ability of the patient to give written informed consent.
  6. Recent history of live attenuated vaccine within 30 days prior to the first dose of study drug.

    Note: Patients, once enrolled, should not receive live vaccine whilst receiving study drug and up to 30 days after the last dose of study drug.

  7. Known current drug or alcohol abuse
  8. Known active or latent tuberculosis (TB) infection (purified protein derivative [PPD] test is not required) as indicated by any of the following: PPD recently converted to positive; chest x-ray with evidence of infections infiltrate.
  9. Hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
  10. Evidence for human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies(
  11. Underlying medical conditions that, in the Principal Investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity determination or adverse events
  12. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of study treatment (either durvalumab monotherapy or durvalumab + Nap combination therapy).

    •Highly effective methods of contraception are defined as one that results in a low failure rate (e.g., less than 1% per year) when used consistently and correctly. Note that some contraception methods are not considered highly effective (e.g., male or female condom with or without spermicide; female cap, diaphragm, or sponge with or without spermicide; non-copper containing intrauterine device; progestogen-only oral hormonal contraceptive pills where inhibition of ovulation is not the primary mode of action [excluding Cerazette/desogestrel which is considered highly effective]; and triphasic combined oral contraceptive pills).

  13. Simultaneous participation in any other study involving investigational drugs or having participated in study less than 4 weeks prior to start of study treatment
  14. History of leptomeningeal carcinomatosis
  15. History of active primary immunodeficiency
  16. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
  17. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Medical Monitor.
  18. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Medical Monitor.
  19. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes apart)
  20. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
  21. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP (Investigational Product). Note: Local surgery of isolated lesions for palliative intent is acceptable.
  22. Patients who have received prior anti-PD-1, anti PD-L1 or anti CTLA-4:

    • Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy.
    • All AEs while receiving prior immunotherapy must have completely resolved or resolved to baseline prior to screening for this study.
    • Must not have experienced a Grade ≥3 immune-related AE or an immune-related neurologic or ocular AE of any grade while receiving prior immunotherapy. Note: Patients with an endocrine AE of Grade ≤2 are permitted to enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic.
    • Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not currently require maintenance doses of >10 mg prednisone or equivalent per day.
  23. Involvement in planning and/or conduct of the study (applies to both sponsor staff and/or staff at the study site).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Ilana Lorber, MD 97239125853 ext 213 ilanal@neotx.com
Contact: Lori Michaeli, MA 072722154556 lori@novatrials.com
Listed Location Countries  ICMJE Israel
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03983954
Other Study ID Numbers  ICMJE 127-CL-01
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party NeoTX Therapeutics Ltd.
Study Sponsor  ICMJE NeoTX Therapeutics Ltd.
Collaborators  ICMJE AstraZeneca Pharmaceuticals PLC
Investigators  ICMJE
Study Director: Ilana Lorber, MD NeoTX Therapeutics Ltd.
PRS Account NeoTX Therapeutics Ltd.
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP