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

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ClinicalTrials.gov Identifier: NCT02403193
Recruitment Status : Recruiting
First Posted : March 31, 2015
Last Update Posted : November 6, 2018
Sponsor:
Collaborators:
Novartis
H. Lee Moffitt Cancer Center and Research Institute
Information provided by (Responsible Party):
Palobiofarma SL

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Non-small Cell Lung Cancer (NSCLC) Drug: PBF-509_80 mg Drug: PBF-509_160 mg Drug: PBF-509_320 mg Drug: PBF-509_640 mg Drug: Combo PBF-509 (160 mg) + PDR001 Drug: Combo PBF-509 (320 mg) + PDR001 Drug: Combo PBF-509 (640 mg) + PDR001 Drug: RP2D (PBF-509+PDR001)_immuno naïve Drug: Experimental: RP2D (PBF-509+PDR001)_immuno treated Phase 1 Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 92 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/Ib Trial of Single Agent PBF-509 and in Combination With PDR001 for Patients With Advanced NSCLC
Study Start Date : October 2015
Estimated Primary Completion Date : October 2020
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: PBF-509_80 mg Drug: PBF-509_80 mg
PBF-509: 80 mg, PO, twice daily (BID)

Experimental: PBF-509_160 mg Drug: PBF-509_160 mg
PBF-509: 160 mg, PO, twice daily (BID)

Experimental: PBF-509_320 mg Drug: PBF-509_320 mg
PBF-509: 320 mg, PO, twice daily (BID)

Experimental: PBF-509_640 mg Drug: PBF-509_640 mg
PBF-509: 640 mg, PO, twice daily (BID)

Experimental: PBF509_160 mg +PDR001 Drug: Combo PBF-509 (160 mg) + PDR001
Drug 1: PDR001 administered intravenously. Drug 2: PBF-509 administered orally

Experimental: PBF509_320 mg+PDR001 Drug: Combo PBF-509 (320 mg) + PDR001
Drug 1: PDR001 administered intravenously. Drug 2: PBF-509 administered orally

Experimental: PBF509_640 mg +PDR001 Drug: Combo PBF-509 (640 mg) + PDR001
Drug 1: PDR001 administered intravenously. Drug 2: PBF-509 administered orally

Experimental: RP2D (PBF-509+PDR001)_immuno naïve
Immunotherapy naïve patients will be treated at the combination RP2D previously determined in the phase Ib, dose escalation portion of the trial.
Drug: RP2D (PBF-509+PDR001)_immuno naïve
Drug 1: PDR001 administered intravenously. Drug 2: PBF509 administered orally

Experimental: RP2D (PBF-509+PDR001)_immuno treated
Patients 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.
Drug: Experimental: RP2D (PBF-509+PDR001)_immuno treated
Drug 1: PDR001 administered intravenously. Drug 2: PBF509 administered orally




Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) of PBF-509 as single agent [ Time Frame: 28 days ]
    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.

  2. Maximum Tolerated Dose (MTD) of the combination (PBF-509+PDR001) treatment [ Time Frame: 56 days ]
    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 PDR001 and 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 :
  1. Time to PBF-509 peak concentration in plasma "Tmax" [ Time Frame: 8 days ]

    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.


  2. Time to PBF-509 peak concentration in plasma at steady state "Tmax,ss" [ Time Frame: 8 days ]

    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.


  3. PBF-509 peak concentration in plasma "Cmax" [ Time Frame: 8 days ]

    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.


  4. PBF-509 peak concentration in plasma at steady state"Cmax,ss" [ Time Frame: 8 days ]

    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.


  5. The area under PBF-509 plasma concentration-time curve to infinite time "AUC(0-inf)" [ Time Frame: 8 days ]

    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


  6. The area under PBF-509 plasma concentration-time curve up to time 't' "AUC(0-t)" [ Time Frame: 8 days ]

    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.


  7. The area under PBF-509 plasma concentration-time curve over the dosing interval "AUC(0-τ)" [ Time Frame: 8 days ]

    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.


  8. PBF-509 half-life in plasma " t½" [ Time Frame: 8 days ]

    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)


  9. PBF-509 apparent volume of distribution following extravascular administration"Vd/F" [ Time Frame: 8 days ]

    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.


  10. PBF-509 total body clearance following extravascular administration "Cl/F" [ Time Frame: 8 days ]

    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.


  11. The PBF 509 accumulation index "Rac" [ Time Frame: 8 days ]

    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.


  12. Efficacy as measured by Objective response rate (ORR) [ Time Frame: 3 years ]

    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.


  13. Efficacy as measured by Disease control rate (DCR) [ Time Frame: 3 years ]

    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


  14. Efficacy as measured by duration of response (DoR) [ Time Frame: 3 years ]
    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.

  15. Efficacy as measured by progression-free survival (PFS) [ Time Frame: 3 years ]
    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.

  16. Efficacy as measured by overall survival (OS) [ Time Frame: 3 years ]
    Overall survival (OS) will be determined as the time from the start of treatment until death due to any cause.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02403193


Contacts
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Contact: Nahomi Castro Palomino, PhD ncastro@palobiofarma.com

Locations
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United States, Florida
H.Lee Moffitt Cancer center Recruiting
Tampa, Florida, United States, 33612
Contact: Alberto Chiappori, MD         
Sponsors and Collaborators
Palobiofarma SL
Novartis
H. Lee Moffitt Cancer Center and Research Institute
Investigators
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Principal Investigator: Alberto Chiappori, MD Moffitt Cancer Center

Additional Information:
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Responsible Party: Palobiofarma SL
ClinicalTrials.gov Identifier: NCT02403193     History of Changes
Other Study ID Numbers: MC18321
First Posted: March 31, 2015    Key Record Dates
Last Update Posted: November 6, 2018
Last Verified: November 2018

Keywords provided by Palobiofarma SL:
Adenosine A2a receptor antagonist
NSCLC
PBF-509
Immunotherapy
adenosine
PDR001
immune checkpoint inhibitors
Programmed Death-1 (PD-1) receptor
Adenosine A2a receptor (A2AR)

Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Adenosine
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Arrhythmia Agents
Vasodilator Agents
Purinergic P1 Receptor Agonists
Purinergic Agonists
Purinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action