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.
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
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
- 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
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
- 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+
- 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
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.
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.
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
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
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
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
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
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.