Clinical Trials /

Pembrolizumab + Imprime PGG for Metastatic Non-small Cell Lung Cancer After Progression on First-Line Therapy: Big Ten Cancer Research Consortium BTCRC-LUN15-017

NCT03003468

Description:

This is an open label, multi-institutional, single arm study with a dose escalation phase Ib cohort, followed by a phase II cohort of pembrolizumab and Imprime PGG. No randomization or blinding is involved.

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

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab + Imprime PGG for Metastatic Non-small Cell Lung Cancer After Progression on First-Line Therapy: Big Ten Cancer Research Consortium BTCRC-LUN15-017
  • Official Title: A Phase Ib/II Study of Anti-PD-1 Antibody Pembrolizumab and Imprime PGG for Patients With Metastatic Non-small Cell Lung Cancer After Progression on First-Line Therapy: Big Ten Cancer Research Consortium BTCRC-LUN15-017

Clinical Trial IDs

  • ORG STUDY ID: BTCRC-LUN15-017
  • NCT ID: NCT03003468

Conditions

  • Non-Small Cell Lung Cancer

Interventions

DrugSynonymsArms
Imprime PGGArm A - Phase Ib
MK-3475pembrolizumab, KeytrudaArm A - Phase Ib
Imprime PGGArm A - Phase Ib

Purpose

This is an open label, multi-institutional, single arm study with a dose escalation phase Ib cohort, followed by a phase II cohort of pembrolizumab and Imprime PGG. No randomization or blinding is involved.

Detailed Description

      OUTLINE: This is a multi-center study.

      The phase Ib dose escalation will evaluate the combination of pembrolizumab and Imprime PGG
      for subjects with metastatic non-small cell lung cancer (NSCLC) after progression on
      first-line platinum-based chemotherapy. The phase II trial will test whether addition of
      Imprime PGG to pembrolizumab will increase median progression-free survival (PFS) in second
      line therapy setting in NSCLC.

      PHASE Ib DOSE ESCALATION INVESTIGATIONAL TREATMENT:

      Cohort 1 will consist of 3-6 patients who will receive

        -  Imprime PGG 2 mg/kg IV on Days 1, 8, 15 for Cycles 1-4

        -  Imprime PGG 2 mb/kg IV on Day 1 for Cycles 5-16

        -  Pembrolizumab 200 mg IV on Day 1 (cycle = 21 days)

      Cohort 2 will consist of 3-6 patients who will receive

        -  Imprime PGG 4 mg/kg IV on Days 1, 8, 15 for Cycles 1-4

        -  Imprime PGG 2 mb/kg IV on Day 1 for Cycles 5-16

        -  Pembrolizumab 200 mg IV on Day 1 (cycle = 21 days)

      If none of the 3 subjects experience a dose limiting toxicity (DLT) during the first cycle of
      therapy, an additional three subjects will be enrolled at dose level 2. If all subjects in
      dose level 2 complete the first cycle of therapy without DLT, 3 more subjects will be
      enrolled into dose level 2 to ensure only 0-1 of 6 subjects have a DLT. There will be no
      further escalation beyond dose level 2.

      PHASE II INVESTIGATIONAL TREATMENT:

      Pembrolizumab will be given on Day 1 of each 21 day cycle after Imprime PGG, and the RP2D
      dose of Imprime PGG will be given on Days 1, 8 and 15 of each 21 day cycle. Treatment will
      continue up to 16 cycles, or until disease progression, unacceptable toxicity, subject
      refusal, or subject death either from progression of disease, the therapy itself, or from
      other causes.

      Life expectancy: of 6 months or greater

      The following baseline labs must be completed within 28 days prior to registration for
      protocol therapy:

      Hepatic:

        -  total bilirubin ≤ 1.5 × upper limit of normal (ULN) OR direct bilirubin ≤ ULN for
           subjects with total bilirubin levels > 1.5 x ULN (except subject with Gilbert's
           Syndrome, who can have total bilirubin < 3.0 mg/dl)

        -  aspartate aminotransferase (AST) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with known
           hepatic metastases

        -  alanine aminotransferase (ALT) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with known hepatic
           metastases

      Renal:

        -  Serum creatinine ≤ 3 mg/dL OR

        -  if serum creatinine > 3mg/dL, estimated glomerular filtration rate (GFR) ≥ 20 mL/min

      Hematopoietic:

        -  hemoglobin ≥ 9 g/dL, subjects requiring transfusion will not be eligible to start study

        -  and absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L

        -  and platelet count ≥ 100 × 10^9/L

      Coagulation:

        -  INR < 1.5 × ULN OR

        -  for subjects receiving anticoagulant, the subjects must, in the investigator's opinion,
           be clinically stable with no evidence of active bleeding while receiving anticoagulant
           therapy. The INR for subjects on warfarin should be in the therapeutic range. Low
           molecular weight heparin (LMWH) is allowed.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A - Phase IbExperimentalDose Escalation Cohort Cohort 1 will consist of 3-6 patients who will receive pembrolizumab 200mg IV on Day 1 of each 21 day cycle. Imprime PGG will be administered at 2mg/kg on Day 1,8, and 15 of cycles 1-4, and on Day 1 of cycles 5-16. On Day 1 of each cycle, the Imprime PGG intravenous infusion is given first followed 15-30 minutes later by the pembrolizumab. Experimental: Arm A - Phase II Investigational Treatment The maximum safe dose of Imprime PGG in combination with pembrolizumab (as determined in the phase Ib cohort) will be given on Day 1,8, and 15 for cycles 1-4, and on Day 1 of cycles 5-16. Cohort 2 will consist of 3-6 patients who will receive pembrolizumab 200mg IV on Day 1 and Imprime PGG at 4mg/kg on Day 1,8, and 15 for Cycles 1-4 and on Day 1 only for Cycles 5-16. On Day 1 of each cycle, the Imprime PGG intravenous infusion is given first followed 15-30 minutes later by the pembrolizumab.
  • Imprime PGG
  • MK-3475
  • Imprime PGG

Eligibility Criteria

        Inclusion Criteria:

          -  Male or female ≥ 18 years of age at time of consent.

          -  Subjects with histologically or cytologically confirmed non-small cell lung cancer
             (NCSLC).

          -  Subjects with stage IV non-small cell lung cancer as defined by American Joint
             Committee on Cancer (AJCC).

          -  Phase Ib: Subjects who progressed after first-line platinum-based chemotherapy and who
             are candidates for second-line therapy.

          -  Phase II: Subjects who have progressed on first-line systemic therapy (either
             platinum-based chemotherapy with or without immune checkpoint inhibitor or immune
             checkpoint inhibitor as first line therapy) who are candidates for second-line
             systemic therapy.

          -  Phase II: Subjects with an EGFR or ALK mutation who are no longer candidates for TKI
             therapy and have progressed on standard systemic therapy (either platinum-based
             chemotherapy with or without immune checkpoint inhibitor or immune checkpoint
             inhibitor as first line therapy).

          -  Phase II only: Measurable disease according to RECIST v1.1 (Section 8) obtained by
             imaging within 28 days prior to study registration. Phase Ib: subjects may enroll with
             or without measurable disease.

          -  Phase II only: Subjects must have presence of peripheral blood levels of IgG
             anti-β-glucan antibody (ABA) of ≥ 20 μg/mL as determined by an ELISA test within 90
             days prior to study registration.

          -  Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
             within 28 days prior to study registration.

          -  Life expectancy of 6 months or greater as determined by the treating physician.

          -  Adequate hepatic function within 28 days prior to study registration defined as
             meeting all of the following criteria:

               -  total bilirubin ≤ 1.5 × upper limit of normal (ULN) OR direct bilirubin ≤ ULN for
                  subjects with total bilirubin levels > 1.5 x ULN (except subject with Gilbert's
                  Syndrome, who can have total bilirubin < 3.0 mg/dl)

               -  aspartate aminotransferase (AST) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with known
                  hepatic metastases

               -  alanine aminotransferase (ALT) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with known
                  hepatic metastases

          -  Adequate renal function within 28 days prior to study registration defined by either
             of the following criteria:

               -  Serum creatinine ≤ 3 mg/dL

               -  if serum creatinine > 3mg/dL, estimated glomerular filtration rate (GFR) ≥ 20
                  mL/min

          -  Adequate hematologic function within 28 days prior to study registration defined as
             meeting all of the following criteria:

               -  hemoglobin ≥ 9 g/dL; subjects requiring transfusion will be eligible to start
                  study

               -  and absolute neutrophil count (ANC) ≥ 1.5 × 109/L

               -  and platelet count ≥ 100 × 109/L

          -  Adequate coagulation functioning within 28 days prior to study registration defined by
             either of the following criteria:

               -  INR < 1.5 × ULN

               -  for subjects receiving anticoagulant, the subjects must, in the investigator's
                  opinion, be clinically stable with no evidence of active bleeding while receiving
                  anticoagulant therapy. The INR for subjects on warfarin should be in the
                  therapeutic range. Low molecular weight heparin (LMWH) is allowed.

          -  Provided written informed consent and HIPAA authorization for release of personal
             health information, approved by an Institutional Review Board (IRB). NOTE: HIPAA
             authorization may be included in the informed consent or obtained separately.

          -  Women of childbearing potential (WOCP) must not be pregnant or breast-feeding. A
             negative serum or urine pregnancy test is required within 72 hours of study
             registration. If the urine test cannot be confirmed as negative, a serum pregnancy
             test will be required.

          -  Women of childbearing potential (WOCP) must be willing to use two effective methods of
             birth control such as an oral, implantable, injectable, or transdermal hormonal
             contraceptive, an intrauterine device (IUD), use of a double barrier method (condoms,
             sponge, diaphragm, or vaginal ring with spermicidal jellies or cream), or total
             abstinence for the course of the study until 120 days after the last dose of study
             drug. NOTE: Women are considered to be of childbearing potential unless they are
             postmenopausal (≥45 years of age and has not had menses for greater than 12
             consecutive months), surgically sterile (bilateral tubal ligation, bilateral
             oophorectomy, or hysterectomy) or not heterosexually active for the duration of the
             study and at least 120 days after the last dose of study drug.

          -  Men who are not surgically sterile (vasectomy) must agree to use an acceptable method
             of contraception. Male subjects with female sexual partners who are pregnant, possibly
             pregnant, or who could become pregnant during the study must agree to use condoms from
             the first dose of study drug through at least 120 days after the last dose of study
             drug. Total abstinence for the same study period is an acceptable alternative.

          -  Willingness and ability to comply with scheduled visits (including geographical
             distance), treatment plans, laboratory tests, and other study procedures.

        Exclusion Criteria:

          -  Surgery within 4 weeks prior to study registration except for minor procedures. NOTE:
             Hepatic biliary stent placement is allowed. NOTE: Subject must have adequately
             recovered from the toxicity and/or complications of major surgery prior to study
             registration, as determined by the treating physician.

          -  Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
             Subjects with neurological symptoms must undergo a head CT scan or brain MRI to
             exclude brain metastasis. NOTE: Subjects with previously treated brain metastases may
             participate provided

          -  they are stable (without evidence of progression by imaging for at least four weeks
             prior to the first dose of trial treatment and any neurologic symptoms have returned
             to baseline),

          -  have no evidence of new or enlarging brain metastases, and

          -  are not using steroids for at least 7 days prior to study registration. This exception
             does not include carcinomatous meningitis, which is excluded regardless of clinical
             stability.

          -  Previously received a solid organ transplant or allogeneic progenitor/stem cell
             transplant.

          -  Received a live vaccine within 30 days prior to the first dose of trial treatment.
             Examples of live vaccines include, but are not limited to: measles, mumps, rubella,
             chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza
             vaccines for injection are generally killed virus vaccines and are allowed; however,
             intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines and are
             not allowed.

          -  History of blood clots, pulmonary embolism, or deep vein thrombosis unless on adequate
             anticoagulant therapy as determined by the treating investigator (subject must be on
             stable dose for 2 weeks).

          -  Known history of human immunodeficiency virus [(HIV) HIV 1/2 antibodies].

          -  Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
             [qualitative] is detected).

          -  Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other
             form of immunosuppressive therapy within 7 days prior to study registration.

          -  Has active autoimmune disease that has required 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. NOTE: 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.

          -  Received prior chemotherapy, an immune checkpoint inhibitor, or radiation therapy
             within 2 weeks prior to study registration or who has not recovered (i.e., ≤ Grade 1
             or at baseline) from adverse events from previously administered agents. NOTE:
             Subjects with alopecia, grade ≤ 2 sensory neuropathy or other grade ≤ 2 AEs not
             constituting a safety risk based on investigator judgement are an exception to this
             criterion and can still be considered for the study.

          -  Any clinically significant infection defined as any acute viral, bacterial, or fungal
             infection that requires specific treatment. NOTE: Anti-infective treatment must be
             completed ≥ 7 days prior to study registration.

          -  Has history of (non-infectious) pneumonitis that required steroids, evidence of
             interstitial lung disease or active, non-infectious pneumonitis.

          -  Known history of active tuberculosis.

          -  Any other severe, uncontrolled medical condition, including uncontrolled diabetes
             mellitus (defined as a Hemoglobin A1C ≥ 9% in subjects with a prior history of
             diabetes, 28 days prior to study registration) or unstable congestive heart failure
             (Stage III-IV of the New York Heart Association Functional Classification)

          -  Previous known allergy or intolerance to pembrolizumab or any of its excipients

          -  Previous exposure or known allergy to Imprime PGG or any of its excipients

          -  Known hypersensitivity to Chinese hamster ovary cell products or other recombinant
             human antibodies

          -  Other severe acute or chronic medical or psychiatric condition or laboratory
             abnormality that may increase the risk associated with study participation or
             investigational product administration, interfere with protocol compliance, or may
             interfere with the interpretation of study results and, in the judgment of the
             investigator, would make the subject inappropriate for enrollment in this study.

          -  Presence of any non-healing wound, fracture, or ulcer within 28 days prior to study
             registration.

          -  Any mental or medical condition that prevents the subject from giving informed consent
             or participating in the trial.

          -  No prior malignancy is allowed except for adequately treated basal cell or squamous
             cell skin cancer, in situ cervical cancer, Gleason ≤ grade 7 prostate cancers, or
             other cancer for which the subject has been disease-free for at least 5 years.

          -  Treatment with any therapeutic investigational agent within 28 days prior to study
             registration.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase Ib: Maximum Tolerated Dose
Time Frame:From the start of combination treatment until completion of the first cycle of treatment (21 days)
Safety Issue:
Description:Phase Ib: Maximum tolerated dose (MTD) for subjects receiving Imprime PGG with pembrolizumab without experiencing dose-limiting toxicity(s) (DLT) per Common Terminology Criteria for Adverse Events (CTCAE) v4.

Secondary Outcome Measures

Measure:Adverse Effects
Time Frame:From start of treatment D1 and every treatment visit thereafter (up to 11 months [16 cycles])
Safety Issue:
Description:Number of Participants with Adverse Events as a Measure of Safety and Tolerability per Common Terminology Criteria for Adverse Events (CTCAE) v4.
Measure:Clinical Benefit Ratio
Time Frame:From the start of treatment D1 assessed every 6 weeks +/- 1 week while on study treatment (up to 11 months [16 cycles])
Safety Issue:
Description:Clinical Benefit Ratio (complete, partial response, or stable disease) as assessed per RECIST 1.1.
Measure:Overall Survival (OS)
Time Frame:from the start of the treatment until death from any cause (up to 1 year from start of treatment)
Safety Issue:
Description:To determine the overall survival for this patient population at 1 year.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Lawrence Feldman, MD

Trial Keywords

  • Anti-PD-1
  • Pembrolizumab
  • Imprime PGG
  • MK-3475

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