Clinical Trials /

Study in Patients With Tumours Requiring Arginine to Assess ADI-PEG 20 With Atezolizumab, Pemetrexed and Carboplatin

NCT03498222

Description:

iTRAP is an open-label, multi-centre, dose escalation study of ADI PEG20 in combination with atezolizumab, pemetrexed and carboplatin in patients with advanced non-squamous non-small cell lung carcinoma (NSCLC) - stage IIIB/IV.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study in Patients With Tumours Requiring Arginine to Assess ADI-PEG 20 With Atezolizumab, Pemetrexed and Carboplatin
  • Official Title: Phase I Study in Patients With Tumours Requiring Arginine to Assess ADI-PEG 20 With Atezolizumab, Pemetrexed and Carboplatin (ADIAtezoPemCarbo) (iTRAP Study)

Clinical Trial IDs

  • ORG STUDY ID: 012375QM
  • NCT ID: NCT03498222

Conditions

  • Carcinoma, Non-Small-Cell Lung

Interventions

DrugSynonymsArms
AtezolizumabTecentriqDose Level -1
PemetrexedAlimtaDose Level -1
CarboplatinDose Level -1
ADI PEG20Dose Level -1

Purpose

iTRAP is an open-label, multi-centre, dose escalation study of ADI PEG20 in combination with atezolizumab, pemetrexed and carboplatin in patients with advanced non-squamous non-small cell lung carcinoma (NSCLC) - stage IIIB/IV.

Detailed Description

      iTRAP is an open-label, multi-centre, dose escalation study of ADI PEG20 in combination with
      atezolizumab, pemetrexed and carboplatin in patients with advanced non-squamous NSCLC (stage
      IIIB/IV). Patients will initially receive 4 cycles of ADI PEG20 in combination with
      atezolizumab, pemetrexed and carboplatin unless there is documented disease progression or
      unacceptable toxicities. On completion of 4 cycles and in the absence of disease progression
      requiring other therapeutic interventions, patients may receive additional cycles of ADI
      PEG20 and/or atezolizumab and/or pemetrexed for up to a maximum of 2 years at the discretion
      of the treating physician.

      Dose escalation will occur using a 3 + 3 design. The trial will start at dose level 1, which
      represents 100% of the recommended dose of carboplatin (AUC5) and pemetrexed (500mg/m2) when
      given as a combination, 100% of the atezolizumab recommended dose (1200mg) and 50% of the
      recommended single agent dose of ADI PEG20 (18mg/m2). ADI PEG20 doses will be increased
      according to pre-planned dose escalations.

      If the maximum tolerated dose (MTD) is reached with the first 6 patients, up to an additional
      6 patients will be enrolled at the MTD. The MTD is defined as the dose level below that at
      which 2/3 or ≥3/6 patients experience a dose limiting toxicity (DLT).

      The maximum administered dose (MAD) may also equal the MTD if dose escalation is stopped
      before two DLTs are observed at a given dose level due to the expectation that higher dose
      levels would be too toxic to administer to patients or the maximum planned dose level has
      been achieved.

      The MTD will be determined following review of all the relevant toxicity data by the Safety
      Review Committee (SRC).

      If dose level 1 equals the MAD then dose level -1 may be investigated with a 50% reduction in
      ADI PEG20 (9mg/m2) along with atezolizumab 1200mg, carboplatin AUC5, and pemetrexed 500mg/m2.
    

Trial Arms

NameTypeDescriptionInterventions
Dose Level -1ExperimentalAtezolizumab 1200mg Pemetrexed 500mg/m2 Carboplatin AUC5 ADI PEG20 9mg/m2
  • Atezolizumab
  • Pemetrexed
  • Carboplatin
  • ADI PEG20
Dose Level 1ExperimentalAtezolizumab 1200mg Pemetrexed 500mg/m2 Carboplatin AUC5 ADI PEG20 18mg/m2
  • Atezolizumab
  • Pemetrexed
  • Carboplatin
  • ADI PEG20
Dose Level 2ExperimentalAtezolizumab 1200mg Pemetrexed 500mg/m2 Carboplatin AUC5 ADI PEG20 36mg/m2
  • Atezolizumab
  • Pemetrexed
  • Carboplatin
  • ADI PEG20

Eligibility Criteria

        Inclusion Criteria:

          -  Willing and able to provide written informed consent prior to study entry.

          -  Age ≥ 18 years.

          -  Histologically proven advanced non-squamous NSCLC (stage IIIB/IV) not treated with
             chemotherapy or immunotherapy - immunotherapy for uveal melanoma and prior
             (neo)adjuvant chemotherapy is permitted. Patients with EGFR mutant or ALK positive
             NSCLC must have had an EGFR tyrosine kinase inhibitor (TKI) or ALK inhibitor and
             progressed or been shown to be intolerant of therapy prior to enrolling in this trial.

          -  ASS1 deficiency defined as ≤50% ASS expression on tissue specimen by
             immunohistochemistry (IHC) (cytospin samples are acceptable) - assessed centrally. For
             patients previously treated with (neo)adjuvant chemotherapy, this specimen may have
             been obtained before that chemotherapy.

          -  Measurable disease as assessed by RECIST 1.1 i.e. at least one lesion, not previously
             irradiated, that can be measured accurately at baseline as ≥10 mm in the longest
             diameter (except lymph nodes which must have short axis ≥15 mm) with computed
             tomography (CT) or magnetic resonance imaging (MRI) which is suitable for accurate
             repeated measurements OR lytic or mixed (lytic + sclerotic) bone lesions in the
             absence of measurable disease as defined above; NOTE: patients with sclerotic /
             osteoblastic bone lesions only in the absence of measurable disease are not eligible)

          -  ECOG performance status of 0 - 1

          -  Fully recovered from any prior surgery and no major surgery within 4 weeks of
             initiating study treatment. Surgery for placement of vascular access devices is
             acceptable.

          -  Female patients of childbearing potential and their partners (if male) and male
             patients with female partners of childbearing potential and their partners must agree
             to use a highly effective form of contraception for the duration of the study and
             until 35 days after the final dose of ADI-PEG 20 or 180 days after the final dose of
             atezolizumab, pemetrexed or carboplatin, whichever is later.

          -  Negative serum or urine pregnancy test for female patients of childbearing potential
             within 14 days prior to cycle 1 day 1.

          -  Adequate normal organ, marrow and coagulation function within 28 days prior to cycle 1
             day 1 as defined by the following:

               1. Haemoglobin (HB) > 9.0 g/dL

               2. Absolute neutrophil count (ANC) > 1.5 x 109/L.

               3. Platelets > 75 x 109/L.

               4. Either: (i) serum bilirubin ≤ 1.5 x upper limit of normal (ULN) or (ii) alanine
                  aminotransferase (ALT), aspartate aminotransferase (AST) and/or alkaline
                  phosphatase (ALP) ≤ 3 x (ULN) unless raised due to tumour in which case up to 5 x
                  ULN is permissible.

               5. Serum uric acid ≤ 10 mg/dL (595 µmol/L) (with or without medication control).

               6. Creatinine clearance ≥ 60 mL/min (estimated, using Cockcroft and Gault formula).

          -  Willing and able to comply with the protocol for the duration of the study including
             undergoing treatment, scheduled visits and examinations including follow up.

        Exclusion Criteria:

          -  Radiotherapy (including for palliative reasons) or targeted therapywithin four weeks
             before study treatment.

          -  History of autoimmune disease including but not limited to myasthenia gravis,
             myositis, autoimmune hepatitis, systemic lupus erythematosus (SLE), rheumatoid
             arthritis, inflammatory bowel disease, vascular thrombosis associated with
             antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome,
             Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.
             Patients with the following are eligible:

               1. history of autoimmune-related hypothyroidism on a stable dose of
                  thyroid-replacement hormone

               2. controlled Type 1 diabetes mellitus on a stable insulin dosing regimen

               3. eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic
                  manifestations only (e.g. patients with psoriatic arthritis would be excluded)
                  are permitted provided that they meet the following conditions:

                    -  rash must cover less than 10% of body surface area

                    -  disease is well controlled prior to study entry and only requires low
                       potency topical steroids

                    -  no acute exacerbations of underlying condition within the previous 12 months
                       (not requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate,
                       retinoids, biologic agents, oral calcineurin inhibitors, or high potency or
                       oral steroids).

          -  Ongoing toxic manifestations of previous treatments.

          -  Symptomatic brain or spinal cord metastases (patients must be stable for > 3 months
             post radiotherapy or surgery).

          -  Major thoracic or abdominal surgery from which the patient has not yet recovered.

          -  Serious infection requiring treatment with intravenous antibiotics at the time of
             study entrance, or an infection requiring intravenous therapy within 7 days prior to
             the first dose of study treatment.

          -  Known to be serologically positive for human immunodeficiency virus (HIV).

          -  Known active hepatitis infection (defined as having a positive hepatitis B surface
             antigen [HBsAg] test at screening) or hepatitis C. Patients with past hepatitis B
             virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg
             test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are
             eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if
             polymerase chain reaction (PCR) is negative for HCV RNA.

          -  Uncontrolled serious intercurrent illness including, but not limited to, ongoing or
             active infection, symptomatic congestive heart failure (New York Heart Association
             Class III or IV), cardiac arrhythmia, or psychiatric illness, and social situations
             that would limit compliance with study requirements.

          -  Prior bone marrow transplant or have had extensive radiotherapy to greater than 25% of
             bone marrow within 8 weeks of study treatment.

          -  Ongoing therapeutic anticoagulation (prophylactic dose low molecular weight heparin is
             acceptable).

          -  Concurrent treatment with other experimental drugs or participation in another
             interventional clinical study with therapeutic intent within 28 days from cycle 1 day
             1. Participation in an observational or biomarker study would be acceptable, with
             prior Sponsor approval.

          -  Malignancies other than NSCLC within 5 years prior to study entry, with the exception
             of those with a negligible risk of metastasis or death and treated with expected
             curative outcome.

          -  Prior treatment with cluster of differentiation 137 (CD137) agonists,
             anti-cytotoxic-T-lymphocyte-associated antigen 4 (anti-CTLA4), anti-programmed death-1
             (anti-PD-1), or anti-PD-L1 therapeutic antibody or pathway-targeting agents.

          -  History of severe allergic, anaphylactic, or other hypersensitivity reactions to
             chimeric or humanised antibodies or fusion proteins.

          -  Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster
             ovary cells or to any component of the atezolizumab formulation.

          -  Prior allogeneic stem cell or solid organ transplantation.

          -  History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced
             pneumonitis, organizing pneumonia (i.e. bronchiolitis obliterans, cryptogenic
             organizing pneumonia), or evidence of active pneumonitis on screening chest
             computerised tomography (CT) scan. History of radiation pneumonitis in the radiation
             field (fibrosis) is permitted.

          -  Active tuberculosis.

          -  Receipt of a live, attenuated vaccine within 4 weeks prior to cycle 1 day 1 or
             anticipation that a live, attenuated vaccine will be required during atezolizumab
             treatment or within 5 months after the last dose of atezolizumab.

          -  Treatment with systemic immunostimulatory agents (including but not limited to
             interferons or interleukin [IL]-2) within 4 weeks or five half-lives of the drug
             (whichever is longer) prior to cycle 1 day 1.

          -  Treatment with systemic corticosteroids or other systemic immunosuppressive
             medications (including but not limited to prednisone, dexamethasone, cyclophosphamide,
             azathioprine, methotrexate, thalidomide, mycophenolate and anti-tumour necrosis factor
             [TNF] agents) within 2 weeks prior to cycle 1 day, or anticipated requirement for
             systemic immunosuppressive medications during the trial. Patients who have received
             acute, low dose, systemic immunosuppressant medications (e.g. one-time dose of
             dexamethasone) may be enrolled in the study. During study participation, steroids are
             allowed as per chemotherapy pre-medication only.

          -  Known allergy to platinum salts.

          -  Pregnancy or lactation for female patients.

          -  Patients who had been treated with ADI-PEG 20 previously.

          -  History of seizure disorder not related to underlying cancer.

          -  Known allergy to pegylated compounds.

          -  Known allergy to E. coli drug products (such as GMCSF).

          -  Any other disease, metabolic dysfunction, physical examination finding, or clinical
             laboratory finding that, in the investigator's opinion, gives reasonable suspicion of
             a disease or condition that contraindicates the use of an investigational drug, may
             affect the interpretation of the results, render the patient at high risk from
             treatment complications or interferes with obtaining informed consent.

          -  Psychological, familial, sociological or geographical conditions that do not permit
             compliance with the study protocol.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Occurrence of dose limiting toxicities
Time Frame:First 21 days of treatment
Safety Issue:
Description:Protocol defined haematological events attributed as possibly, probably or definitely related to the study treatment.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Queen Mary University of London

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