Clinical Trials /

Trial of PBF-509 and PDR001 in Patients With Advanced Non-small Cell Lung Cancer (NSCLC)

NCT02403193

Description:

The purpose of this study is to determine the safety, tolerability, feasibility and preliminary efficacy of the administration of PBF-509 (Adenosine A2a receptor antagonist) as single agent or in combination with PDR001 (programmed cell death 1 receptor antibody (PD-1 Ab)) to NSCLC patients.

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

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Trial of PBF-509 and PDR001 in Patients With Advanced Non-small Cell Lung Cancer (NSCLC)
  • Official Title: Phase I/Ib Trial of Single Agent PBF-509 and in Combination With PDR001 for Patients With Advanced NSCLC

Clinical Trial IDs

  • ORG STUDY ID: MC18321
  • NCT ID: NCT02403193

Conditions

  • Non-small Cell Lung Cancer (NSCLC)

Interventions

DrugSynonymsArms
PBF-509_80 mgPBF-509_80 mg
PBF-509_160 mgPBF-509_160 mg
PBF-509_320 mgPBF-509_320 mg
PBF-509_640 mgPBF-509_640 mg
Combo PBF-509 (160 mg) + PDR001PBF509_160 mg +PDR001
Combo PBF-509 (320 mg) + PDR001PBF509_320 mg+PDR001
Combo PBF-509 (640 mg) + PDR001PBF509_640 mg +PDR001
RP2D (PBF-509+PDR001)_immuno naïveRP2D (PBF-509+PDR001)_immuno naïve
Experimental: RP2D (PBF-509+PDR001)_immuno treatedRP2D (PBF-509+PDR001)_immuno treated

Purpose

The purpose of this study is to determine the safety, tolerability, feasibility and preliminary efficacy of the administration of PBF-509 (Adenosine A2a receptor antagonist) as single agent or in combination with PDR001 (programmed cell death 1 receptor antibody (PD-1 Ab)) to NSCLC patients.

Detailed Description

      A single institution phase I/Ib (dose escalation plus expansion) clinical trial of PBF-509
      and combination treatment of PDR001 plus PBF-509 in Eastern Cooperative Oncology Group (ECOG)
      0-1 patients with immunotherapy naïve and pretreated, advanced or metastatic NSCLC will be
      conducted to evaluate the safety, tolerability and preliminary efficacy of the combination.

      The main objectives of the proposed Phase I trial will be:

      Phase I Dose Escalation:

        -  To determine the safety and tolerability of PBF-509 during a phase I dose escalation
           trial

        -  Determine the pharmacokinetic profile of PBF-509

        -  Determine the safety profile of PBF-509

      Phase 1 Dose Expansion:

      • To further determine safety and tolerability of PBF-509 at the recommended phase II dose
      (RP2D)

      Phase Ib Dose Escalation:

        -  To determine the dose limiting toxicities (DLT), maximum tolerated dose (MTD) and
           recommended phase II dose (RP2D) of PBF-509 in combination with PDR001

        -  To determine the pharmacokinetics (PK) of PBF-509 in combination with PDR001

      Phase Ib Expansion:

        -  To determine the safety and tolerability of PBF-509 in combination with PDR001, at the
           RP2D, in both immunotherapy naïve and pretreated advanced NSCLC

        -  To evaluate the response rate (ORR) of PBF-509 in combination with PDR001, at the RP2D,
           in both immunotherapy naïve and pretreated advanced NSCLC

        -  To evaluate the progression free (PFS) and overall survival (OS) of PBF-509 in
           combination with PDR001, at the RP2D, in both immunotherapy naïve and pretreated
           advanced NSCLC

        -  To determine the pharmacokinetics (PK) of PBF-509 in combination with PDR001

      Correlative (Exploratory) Studies:

        -  To evaluate the biological activity of PBF-509 alone and in combination with PDR001 by
           assessment of potential pharmacodynamic (PD) biomarkers in tumor biopsy specimens of
           patients with advanced NSCLC

        -  To determine association of pre- or on-treatment expression of other immune checkpoints
           genes with resistance to single agent PBF-509 and dual immune inhibitory (PDR001+
           PBF-509) treatment.

        -  Determine the pharmacokinetics of PDR001 in combination with PBF-509

      The phase I and phase Ib dose escalations will be conducted utilizing the standard 3+3 dose
      escalation method. Pharmacokinetic (PK) data will be obtained for PBF-509 and PDR001.

      The phase Ib dose expansion will consist of 2 independent groups of immunotherapy naïve and
      pretreated (previous immune checkpoint inhibitors; anti-CTLA-4, anti-PD-1, anti-PD-L1 and/or
      combinations) patients. Pharmacodynamic (PD) data will be obtained for potential biomarker
      analysis with pre-treatment and on-treatment tumor biopsies.

      Number of Patients:

      Phase I Dose escalation and safety expansion: 15-18 patients will be treated with single
      agent PBF-509 in escalation and up to 20 patients may be treated at the RP2D as a safety
      expansion group.

      Phase Ib Dose escalation: 15-24 patients will be treated

      The specific number of patients enrolled will vary depending on whether additional patients
      could be required during the escalation period if dose de-escalation cohorts or intermediate
      doses are enrolled, or when a dose-escalation cohort is expanded.

      Phase Ib Dose Expansion: 20 patients per group will be enrolled for a total of 40 patients.
      Assuming 10-15% eligibility/screen failures, a maximum 50 patients will be enrolled.

      Safety Assessments:

      The maximun tolerated dose (MTD) evaluation will be based on the dose-limiting toxicity (DLT)
      Evaluable Population which includes all patients enrolled in the dose-escalation portion of
      the trial, who receive the protocol-assigned treatment with PDR001 and PBF-509 and complete
      the safety follow-up through the DLT evaluation period, or experience a DLT during the DLT
      evaluation period.

      The safety evaluation will be based on the treated Population, which includes all patients
      who receive any dose of investigational product, and will include adverse events (AEs),
      serious adverse event (SAEs), laboratory evaluations and electrocardiogram (ECG) results.

      AEs will be graded according to the National Cancer Institute Common Terminology Criteria for
      Adverse Events (NCI CTCAE) v4.03 and described by system organ class and preferred tem using
      the Medical Dictionary for Regulatory Activities (MedDRA). Clinically relevant Laboratory
      abnormalities with toxicity grades according to the NCI CTCAE v4.03 will be derived and
      summarized.

      Efficacy Assessments:

      The efficacy analysis will be based on the treated Population which includes all patients who
      receive any dose of either investigational product. The following efficacy endpoints will be
      analyzed:

        1. Objective Response Rate (ORR) is defined as confirmed complete response (CR) or partial
           response (PR) based on modified Response Evaluation Criteria in Solid Tumors (RECIST)
           v1.1. Disease control rate (DCR) is defined as CR, PR, or stable disease (SD) based on
           modified RECIST v1.1.

        2. Duration of response (DoR) is defined as the duration from the first documentation of
           Objective response (OR) to the first documented disease progression or death due to any
           cause, whichever occurs first.

        3. Progression-free survival (PFS) will be measured from the start of treatment until the
           documentation of disease progression or death due to any cause, whichever occurs first.

        4. Overall survival (OS) will be determined as the time from the start of treatment with
           PDR001 and PBF-509 until death due to any cause
    

Trial Arms

NameTypeDescriptionInterventions
PBF-509_80 mgExperimental
  • PBF-509_80 mg
PBF-509_160 mgExperimental
  • PBF-509_160 mg
PBF-509_320 mgExperimental
  • PBF-509_320 mg
PBF-509_640 mgExperimental
  • PBF-509_640 mg
PBF509_160 mg +PDR001Experimental
  • Combo PBF-509 (160 mg) + PDR001
PBF509_320 mg+PDR001Experimental
  • Combo PBF-509 (320 mg) + PDR001
PBF509_640 mg +PDR001Experimental
  • Combo PBF-509 (640 mg) + PDR001
RP2D (PBF-509+PDR001)_immuno naïveExperimentalImmunotherapy naïve patients will be treated at the combination RP2D previously determined in the phase Ib, dose escalation portion of the trial.
  • RP2D (PBF-509+PDR001)_immuno naïve
RP2D (PBF-509+PDR001)_immuno treatedExperimentalPatients previously treated with immunotherapy (previous immune checkpoint inhibitors; anti-CTLA-4, anti-PD-1, anti-PD-L1 and/or combinations) will be treated at the combination RP2D previously determined in the phase Ib, dose escalation portion of the trial.
  • Experimental: RP2D (PBF-509+PDR001)_immuno treated

Eligibility Criteria

        Inclusion Criteria:

          1. Patients must have histologic or cytologic diagnosis of advanced/metastatic NSCLC. For
             those with mixed histology, there must be a predominant histology.

          2. Patients must previously have received at least one prior line of therapy for their
             disease

          3. EGFR mutation with exon 19 deletion or L858R mutation (Exon 21) or ALK rearrangement
             positive must have failed prior TKI therapy

          4. Able, willing to give written consent for available archival tumor samples (not
             mandatory) and tumor biopsies before and during protocol therapy (mandatory).

          5. Prior immunotherapy is allowed (previous immune checkpoint inhibitors; anti-CTLA-4,
             anti-PD-1, anti-PD-L1 and/or combinations), except for the patients enrolled to the
             immunotherapy naïve group of the phase IB dose expansion.

          6. Measurable disease, defined as at least one lesion that can be accurately measured in
             at least one dimension (longest diameter to be recorded for non-nodal lesions and
             short axis for nodal lesions) as >20 mm with conventional techniques or as >10 mm with
             spiral computed tomography (CT) scan, Magnetic resonance imaging (MRI), or calipers by
             clinical exam. See Section 13.

          7. Written informed consent and any locally-required authorization obtained from the
             subject prior to performing any protocol-related procedures, including screening
             evaluations

          8. Age > 18 years at time of study entry

          9. Eastern Cooperative Oncology Group (ECOG) 0-1

         10. Adequate normal organ and marrow function

         11. Female patients must either be of non-reproductive potential (ie, post-menopausal by
             history: ≥60 years old or no menses for 1 year without an alternative medical cause;
             OR history of complete hysterectomy, OR history of bilateral tubal ligation, OR
             history of bilateral oophorectomy) or must have a negative serum pregnancy test upon
             study entry.

         12. Women of child-bearing potential, defined as all women physiologically capable of
             becoming pregnant, must use 2 highly effective methods of contraception while taking
             study treatment and for 90 days after the last dose of study treatment.

         13. Subject is willing and able to comply with the protocol for the duration of the study
             including undergoing treatment and scheduled visits and examinations including follow
             up.

        Exclusion Criteria:

          1. Symptomatic and/or untreated Brain Metastases

          2. Pregnancy or breast feeding

          3. Serious uncontrolled medical disorder or active infection that in the investigator's
             opinion would impair the patient's ability to receive study treatment.

          4. Concurrent use of other anticancer approved or investigational agents is not allowed.

          5. Active or prior documented autoimmune disease within the past 2 years. NOTE: Patients
             with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within
             the past 2 years) are not excluded.

          6. Prior malignancy in past 2 years or as identified in Section 7.2 of this protocol

          7. Patients receiving systemic steroids ≥ 10mg/day of prednisone or the equivalent

          8. Smoking (cigarettes, cigars or pipes) must be discontinued at least 7 days prior to
             initiating study drug administration; smoking cessation products (transdermal nicotine
             patches or chewing gum may be used)

          9. Concurrent administration of strong inhibitors or moderate inducers of CYP1A2 is not
             permitted; administration must be discontinued at least 7 days prior to initiating
             study drug administration.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD) of PBF-509 as single agent
Time Frame:28 days
Safety Issue:
Description:The MTD evaluation will be based on the DLT Evaluable Population which includes all patients enrolled in the dose-escalation portion of the trial, who receive the protocol-assigned treatment with PBF-509 and complete the safety follow-up through the DLT evaluation period, or experience a DLT during the DLT evaluation period.

Secondary Outcome Measures

Measure:Time to PBF-509 peak concentration in plasma "Tmax"
Time Frame:8 days
Safety Issue:
Description:The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the time (in minutes) to reach the maximum "PBF-509" concentration in plasma samples of patients after oral administration of PBF-509.
Measure:Time to PBF-509 peak concentration in plasma at steady state "Tmax,ss"
Time Frame:8 days
Safety Issue:
Description:The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the time (in minutes) to reach the maximum "PBF-509" concentration in plasma samples of patients during a dosing interval at steady state.
Measure:PBF-509 peak concentration in plasma "Cmax"
Time Frame:8 days
Safety Issue:
Description:The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the maximum plasma concentration (ng/mL) of PBF-509 observed after administration.
Measure:PBF-509 peak concentration in plasma at steady state"Cmax,ss"
Time Frame:8 days
Safety Issue:
Description:The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the maximum plasma concentration (ng/mL) of PBF-509 observed during a dosing interval at steady state.
Measure:The area under PBF-509 plasma concentration-time curve to infinite time "AUC(0-inf)"
Time Frame:8 days
Safety Issue:
Description:The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the area under the concentration-time curve from zero up to ∞ with extrapolation of the terminal phase. "AUC(0-inf)" will be given in Amount·time/ volume units
Measure:The area under PBF-509 plasma concentration-time curve up to time 't' "AUC(0-t)"
Time Frame:8 days
Safety Issue:
Description:The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the area under the concentration-time curve from zero up to a definite time t. "AUC(0-t)" will be given in Amount·time/ volume units.
Measure:The area under PBF-509 plasma concentration-time curve over the dosing interval "AUC(0-τ)"
Time Frame:8 days
Safety Issue:
Description:The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the area under the concentration-time curve over the dosing interval. "AUC(0-τ)" will be given in Amount·time/ volume units.
Measure:PBF-509 half-life in plasma " t½"
Time Frame:8 days
Safety Issue:
Description:The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the terminal half-life of PBF-509 in plasma. "t½" will be given in hours (h)
Measure:PBF-509 apparent volume of distribution following extravascular administration"Vd/F"
Time Frame:8 days
Safety Issue:
Description:The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the apparent volume of distribution during terminal phase after oral / extravascular administration. "Vd/F" will be given in Volume or volume/kg units.
Measure:PBF-509 total body clearance following extravascular administration "Cl/F"
Time Frame:8 days
Safety Issue:
Description:The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the apparent total plasma or serum clearance of drug after oral administration. "Cl/F" will be given in the Volume/ time or volume/ time/ kg units.
Measure:The PBF 509 accumulation index "Rac"
Time Frame:8 days
Safety Issue:
Description:The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the accumulation ratio calculated from Cmax,ss at steady state and Cmax after single dosing.
Measure:Efficacy as measured by Objective response rate (ORR)
Time Frame:3 years
Safety Issue:
Description:ORR: Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). ORR is defined as confirmed complete response (CR) or partial response (PR) based on modified RECIST v1.1.
Measure:Efficacy as measured by Disease control rate (DCR)
Time Frame:3 years
Safety Issue:
Description:The disease control rate (DCR) will be estimated considering the following variables: Complete response (CR), Partial response (PR) and stable disease (SD) as described by Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). These variables will be assessed based on Imaging-based evaluation methods as chest x-ray, conventional computed tomography (CT) and magnetic resonance imaging (MRI) that will be performed every 2 cycles of 28 days administration
Measure:Efficacy as measured by duration of response (DoR)
Time Frame:3 years
Safety Issue:
Description:Duration of response (DoR) is defined as the duration from the first documentation of OR to the first documented disease progression or death due to any cause, whichever occurs first.
Measure:Efficacy as measured by progression-free survival (PFS)
Time Frame:3 years
Safety Issue:
Description:Progression-free survival (PFS) will be measured from the start of treatment until the documentation of disease progression or death due to any cause, whichever occurs first. For subjects who are alive and progression-free at the time of data cut-off for analysis, PFS will be censored at the last tumor assessment date.
Measure:Efficacy as measured by overall survival (OS)
Time Frame:3 years
Safety Issue:
Description:Overall survival (OS) will be determined as the time from the start of treatment until death due to any cause.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Palobiofarma SL

Trial Keywords

  • Adenosine A2a receptor antagonist
  • NSCLC
  • PBF-509
  • Immunotherapy
  • adenosine
  • PDR001
  • immune checkpoint inhibitors
  • Programmed Death-1 (PD-1) receptor
  • Adenosine A2a receptor (A2AR)

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