MC# 18-12 - A Phase I/II Study of Pegzilarginase (AEB1102, Co-ArgI-PEG) in Combination with Pembrolizumab in the Treatment of Patients with Extensive Disease (ED) Small Cell Lung Cancer (SCLC)

  • Agent(s): Pegzilarginase, Pembrolizumab
  • Disease Type(s): Lung-SCLC
  • Phase(s): I, II
  • Drug Classification(s): Targeted Therapy, Cellular Therapy
  • Molecular Target(s): Argenine

Mechanism of Action

Pegzilarginase (AEB1102) restricts arginine, an amino acid that certain tumor types have a dependence on for a diverse number of cellular functions including growth and metastasis.

Purpose

 In this study, the sponsor and investigators want to learn:

  • About the safety and tolerability of Pegzilarginase when given with Pembrolizumab
  • How much Pegzilarginase, when given with Pembrolizumab  is absorbed into the blood and how fast it is removed
  • If research tests can be used in the future to predict who will benefit from receiving Pegzilarginase when given with Pembrolizumab
  • How proteins that indicate the status of disease are affected with use of Pegzilarginase when given with Pembrolizumab
  • If the body develops proteins that work against Pegzilarginase or Pembrolizumab when given in combination
  • If Pegzilzrginase, when given with Pembrolizumab, prevents or delays tumor growth or shrinks an existing tumor
Inclusion Criteria
  • Patient is able and willing to provide written informed consent and to comply with all requirements of study participation (including all study procedures) prior to any screening procedures
  • Be > 18 years of age on day of signing informed consent
  • Have histologically or cytologically confirmed SCLC that meet the following corresponding requirements:
    • ED per criteria of the International Association for the Study of Lung Cancer (IASLC)-American Joint Committee on Cancer (AJCC) TNM staging system
    • Have not tolerated or have progressed or relapsed on or within 6 months of platinum- based chemotherapy
  • Have a performance status of ≤ 1 on the ECOG Performance Scale
  • Have measurable disease based on RECIST 1.1 as determined by the site study team. Tumor lesions in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions
  • Willing to undergo core needle or incisional biopsy to obtain fresh tumor tissue specimens. For patients without accessible tumor for biopsy, an archived, formalin-fixed paraffin embedded (FFPE) tumor tissue specimen may be acceptable if it was obtained after the last cancer-directed treatment and tumor is confirmed to be present in the specimen. If an archived FFPE block is provided this needs to be not older than 3 years. In addition, if pre-cut unstained slides are provided these need to be not older than 6 months.
  • Demonstrate adequate organ function, with specimens collected within 10 days prior to day 1 of cycle 1, as defined as:
    • Absolute neutrophil count (ANC) ≥1,500 /mcL
    • Platelets ≥100,000 / mcL (without need of transfusion for at least 14 days prior to scheduled C1D1)
    • Hemoglobin ≥9 g/dL or ≥5.6 mmol/L (without need of erythropoietin or transfusion for at least 14 days prior to scheduled C1D1)
    • Renal: serum creatinine ≤1.5 X upper limit of normal (ULN)
      • Subjects with creatinine levels > 1.5x ULN may qualify if Glomerular Filtration Rate (GFR) OR calculated creatinine clearance per institutional standard (CrCL) are ≥ 60 mL/min/1.73m2
    • Hepatic: serum total bilirubin ≤ 1.5 X ULN
      • Subjects with total bilirubin > 1.5 ULN if direct bilirubin ≤ ULN
      • AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN or ≤ 5 X ULN for patients with liver metastases
      • Albumin ≥ 2.5 mg/dL
      • International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 X ULN
        • Exception: subjects receiving anticoagulant therapy if PT or INR is within therapeutic range of intended use.
      • Activated partial thromboplastin time (aPTT) ≤ 1.5 X ULN
        • Exception: subjects receiving anticoagulant therapy if PTT is within therapeutic range of intended use
  • Subjects must have recovered from the effects (except alopecia or neuropathy) of any prior systemic therapy, radiotherapy or surgery to Grade 1 or less
  • If subject received major surgery or radiation therapy of > 30 Gy, recovered from the toxicity and/or complications from the intervention is required
  • If female and of child-bearing potential, has a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
  • If a sexually active male or female, must be surgically sterile post-menopausal (defined as female patient with 12 months of spontaneous amenorrhea, or 6 months of spontaneous amenorrhea with serum FSH levels higher than 40 mIU/ml, or 6 weeks after bilateral surgical oophorectomy), or must agree to use a physician-approved method of birth control during the study through a minimum of 120 days after the last study drug administration
Exclusion Criteria
  • Has received more than 2 platinum-based regimens against SCLC
  • Has received pembrolizumab, or prior therapy with an anti-PD-1, anti-PD-L1, anti-PD- L2, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody as part of any previous therapy, including trials
  • Has participated in Merck MK-3475 (pembrolizumab) clinical trials
  • Has received pegzilarginase as part of any previous therapy
  • Is currently participating in a study of an investigational agent or and received the last dose within 4 weeks of the first dose of treatment (a shorter interval for kinase inhibitors or other short half-life drugs could be considered after approval from the Sponsor). Is currently participating in a study of an investigational device within 4 weeks of the first dose of treatment.
  • Has a diagnosis of an immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. The use of topical, short courses (3 days or less), or physiologic doses of corticosteroids (doses not higher than 10 mg daily of prednisone equivalent) may be allowed after consultation with the Sponsor.
  • Has had a prior monoclonal antibody (mAb) within 4 weeks prior to first dose or who has not recovered (i.e., ≤ Grade 1) from adverse reactions due to agents administered more than 4 weeks earlier
  • Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to first dose or who has not recovered (i.e., ≤ Grade 1 or at baseline) from treatment-emergent adverse reactions due to a previously administered agent. Note: Patients with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an exception to this criterion and may qualify for the study after consultation with the Sponsor. If the patient has received prior radiation therapy, participant must has recovered from all radiation-related toxicities, not currently taking systemic corticosteroids due to radiation-related toxicities, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (<2 weeks of radiotherapy) to non-CNS disease.
  • If the patient has undergone major surgery, he/she must have recovered adequately from the toxicity and/or complications prior to starting therapy
  • Has received transfusion of blood products (including platelets or red blood cells) or administration of colony stimulating factors (including G-CSF, GM-CSF or recombinant erythropoietin) within 14 days prior to study first dose
  • Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer) that has undergone potentially curative therapy or in situ cervical cancer
  • Has known central nervous system (CNS) metastases. However, patients with previously treated brain metastases may participate provided neurologic symptoms have stabilized, there is no evidence of new brain metastases or hemorrhage, and they are not using steroids for brain metastases or for complications derived from their treatment for at least 7 days prior to first dose of trial treatment
  • Has known carcinomatous meningitis
  • Has an active autoimmune disease requiring systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs) or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Patients with vitiligo or resolved childhood asthma/atopy are an exception to this rule. Patients that require intermittent use of bronchodilators or local steroid injections will not be excluded from the study. Patients with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study. Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc) is not considered a form of systemic treatment.
  • Has evidence of interstitial lung disease, history of non-infectious pneumonitis that required steroids, or current pneumonitis
  • Has an active infection requiring systemic therapy
  • Inadequately controlled hypertension (defined as systolic blood pressure ≥ 200 mmHg and/or diastolic blood pressure ≥ 120 mmHg) on more than one occasion in the month before planned day of infusion. Patients with more than one episode of inadequately controlled hypertension will be allowed to participate under initiation or modification of antihypertensive treatment provided adequate control (defined as systolic blood pressure
  • < 160 mmHg and/or diastolic blood pressure <100 mmHg) is documented on 3 separate days over in the week before starting treatment
  • Currently taking 3 or more anti-hypertensive medications, including diuretics (If combination tablets are part of the treatment, each active ingredient part of them counts as one)
  • Prior history of hypertensive crisis or hypertensive encephalopathy
  • History of myocardial infarction, unstable angina, cardiac or other vascular stenting, angioplasty, or cardiac or vascular surgery within 6 months prior to day 1 of study treatment
  • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator
  • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
  • Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
  • Has a known history of Human Immunodeficiency Virus (HIV) (positive for HIV p24 antigen or HIV 1/2 antibodies)
  • Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected)
  • Has received a live-virus vaccination within 30 days prior to the planned first dose of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed. Other seasonal flu vaccines that do not contain live virus are permitted
  • Has a known history of active tuberculosis (Bacillus tuberculosis)
  • Has a history of hypersensitivity to PEG or any component of the pegzilarginase formulation
  • Severe hypersensitivity (≥ Grade 3) to any excipient of pegzilarginase or pembrolizumab
  • Has had an allogenic tissue/solid organ transplant

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://clinicaltrials.gov/ct2/show/NCT03371979?term=NCT03371979&rank=1

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Re: MC# 18-12