Clinical Trials /

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



This is a dose escalation, MTD expansion (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.

Related Conditions:
  • Bladder Carcinoma
  • Breast Carcinoma
  • Cervical Squamous Cell Carcinoma
  • Endometrial Carcinoma
  • Head and Neck Carcinoma
  • Hepatocellular Carcinoma
  • High Grade Ovarian Serous Adenocarcinoma
  • Melanoma
  • Mesothelioma
  • Non-Small Cell Lung Carcinoma
  • Pancreatic Adenocarcinoma
  • Prostate Carcinoma
  • Renal Cell Carcinoma
  • Urothelial Carcinoma
Recruiting Status:



Phase 1

Trial Eligibility



  • Brief Title: Naptulomab Estafenatox in Combination With Durvalumab in Subjects With Selected Advanced or Metastatic Solid Tumors
  • Official Title: Phase 1B, Open-Label, Dose Escalation and Cohort Expansions Trial of Naptulomab Estafenatox (Nap, ABR-217620) in Combination With Durvalumab (MEDI4736) in Subjects With Selected Advanced or Metastatic Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: 127-CL-01
  • NCT ID: NCT03983954


  • 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


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.


        -  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

        -  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.

Trial Arms

Naptumomab estafenatox 2 µg/kg with durvalumabExperimentalNap 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.
    Naptumomab estafenatox 5 µg/kg with durvalumabExperimentalNap 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.
      Naptumomab estafenatox 10 µg/kg with durvalumabExperimentalNap 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.
        Naptumomab estafenatox 15 µg/kg with durvalumabExperimentalNap 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.
          Naptumomab estafenatox 20 µg/kg with durvalumabExperimentalNap 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.
            Expansion pert: Naptumomab estafenatox MTD with durvalumabExperimentalMTD Nap will be given for 3 cycles or more depending on PK results, as described in this protocol.

              Eligibility Criteria

                      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
                             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
                        5. Previous therapy:
                             1. Cytotoxic chemotherapy: There is no limit to the number of prior regimens
                             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
                        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
                        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
                       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
                       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
                       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).
              Maximum Eligible Age:N/A
              Minimum Eligible Age:18 Years
              Eligible Gender:All
              Healthy Volunteers:No

              Primary Outcome Measures

              Measure: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
              Safety Issue:
              Description: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).


              Phase:Phase 1
              Primary Purpose:Interventional
              Overall Status:Not yet recruiting
              Lead Sponsor:NeoTX Therapeutics Ltd.

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