Phase I/II Study of PDR001 in Patients With Advanced Malignancies

Study Overview
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Brief Summary
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The purpose of this first-in-human study of PDR001 was to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of PDR001 administered i.v. as a single agent to adult patients with solid tumors. By blocking the interaction between PD-1 and its ligands, PD-L1 and PD-L2, PDR001 inhibits the PD-1 immune checkpoint, resulting in activation of an antitumor immune response by activating effector T-cells and inhibiting regulatory T-cells.

Detailed Description
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This study was designed as a phase I/II, multi-center, open-label study starting with a phase I dose escalation part followed by a phase II part. Although the study had 2 'arms', the phase I part of the study had 5 dosing cohorts and the phase ll part had 5 treatment groups for a total of 10 reporting groups. PDR001 was administered every 2 weeks until patient experienced unacceptable toxicity, progressive disease per immune related Response Criteria (irRC) and/or treatment was discontinued at the discretion of the investigator or the patient.

Official Title
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Open Label Multicenter Phase I/II Study of the Safety and Efficacy of PDR001 Administered to Patients With Advanced Malignancies

Conditions
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Melanoma, Non-small Sell Lung Cancer (NSCLC), Triple Negative Breast Cancer, Anaplastic Thyroid Cancer, Other Solid Tumors

Intervention / Treatment
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* Biological: PDR001


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent must have been obtained prior to any screening procedures Phase I part: Patients with advanced/metastatic solid tumors, with measurable or non-measurable disease as determined by RECIST version 1.1 (refer to Appendix 1), who have progressed despite standard therapy or are intolerant of standard therapy, or for whom no standard therapy exists. Phase II part: Patients with advanced/metastatic solid tumors, with at least one measurable lesion as determined by RECIST version 1.1, who have progressed following their last prior therapy, and fit into one of the following groups: Group 1a and 1b: NSCLC: Patients with NSCLC must have had disease recurrence or progression during or after no more than one prior systemic chemotherapy regimen (platinum doublet-based) for advanced or metastatic disease. Prior maintenance therapy is allowed (e.g. pemetrexed, erlotinib, bevacizumab). Only patients with EGFR mutation-negative tumor are eligible (defined as negative for exon 19 deletions and for the L858R mutation in EGFR at a minimum; however, if more extensive EGFR mutation testing has been performed, the tumor must not harbor any known activating EGFR mutations in Exons 18-21 in order to be considered EGFR mutation-negative). All patients must be tested for EGFR mutational status and, for ALK translocation status if no mutation is detected in EGFR. Patients with ALK translocation-positive NSCLC must have had disease progression following treatment with a corresponding inhibitor and no more than one systemic chemotherapy regimen (platinum doublet-based), in any sequence. Group 2: Melanoma: All patients must have been tested for BRAF mutations. Patients with V600 mutation positive melanoma must have clinical or radiological evidence of disease progression during or after treatment with a BRAF inhibitor alone or in combination with other agents. Group 3: Triple negatice breast cancer. Group 4: Anaplastic thyroid cancer Patients are not required to have received or progressed on a prior therapy. Patients must not be at short term risk for life threatening complications (such as airway compromise or bleeding from locoregional or metastatic disease). Chemoradiation and/or surgery should be considered prior to study entry for those patients with locally advanced disease if those therapies are considered to be in the best interest of the patient. ECOG Performance Status ≤ 1. Patients must have a site of disease amenable to biopsy, and be a candidate for tumor biopsy. Patient must be willing to undergo a new tumor biopsy at baseline or at molecular pre-screening if applicable, and during therapy on this study. For patients in the phase II part of the study, exceptions may be granted after documented discussion with Novartis. After a sufficient number of paired biopsies are collected, the decision may be taken to stop the collection of biopsies. Exclusion Criteria: History of severe hypersensitivity reactions to other mAbs Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. Active infection requiring systemic antibiotic therapy. HIV infection. Active HBV or HCV infection. Patients with ocular melanoma. Systemic anti-cancer therapy within 2 weeks of the first dose of study treatment. For cytotoxic agents that have major delayed toxicity, e.g. mitomycin C and nitrosoureas, 4 weeks washout period. For patients receiving anticancer immunotherapies such as CTLA-4 antagonists, 6 weeks is indicated as the washout period. Prior PD-1- or PD-L1-directed therapy. Patients requiring chronic treatment with systemic steroid therapy, other than replacement-dose steroids in the setting of adrenal insufficiency. Topical, inhaled, nasal and ophthalmic steroids are not prohibited. Patients receiving systemic treatment with any immunosuppressive medication (other than steroids as described above). Use of any vaccines against infectious diseases (e.g. influenza, varicella, pneumococcus) within 4 weeks of initiation of study treatment. Presence of ≥ CTCAE grade 2 toxicity (except alopecia, peripheral neuropathy and ototoxicity, which are excluded if ≥ CTCAE grade 3) due to prior cancer therapy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: Although the study had 2 'arms', the phase I part of the study had 5 dosing cohorts and the phase ll part had 5 treatment groups for a total of 10 reporting groups.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: patients with solid tumors<br>Phase I Dose escalation cohorts | Biological: PDR001<br>* anti-PD1 antibody<br>|
| Other: Selected tumor types<br>Phase II expansion: Selected tumor types: melanoma, NSCLC, triple negative breast cancer, anaplastic thyroid cancer | Biological: PDR001<br>* anti-PD1 antibody<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase l: The Exposure (AUC(0-336h)) After First Dose of Treatment at Cycle 3 (Each Cycle = 28 Days) | Estimated the recommended phase 2 dose (RP2D) and/or the maximum tolerated dose (MTD) for PDR001. AUC0-336h is the AUC from time zero to 336 hour post dose of a measurable concentration sampling time. | Predose, 1hour (h), 24h, 48h, 72h, 168h, 240h, 336h post dose (cycle 3) | 
| Phase l: Incidence of Dose Limiting Toxicities (DLTs) | DLT is defined as an adverse event (AE) or abnormal laboratory value of common terminology criteria for adverse events (CTCAE) grade ≥ 3 assessed as unrelated to disease, disease progression, inter-current illness or concomitant medications, which occurs within the first cycle of treatment with PDR001 during the dose escalation part of the study for which relationship to study treatment cannot be ruled out, with some exceptions. | 8 months | 
| Phase ll: Overall Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) | ORR is the percentage of participants with a best overall response of complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 CR = at least 2 determinations of CR at least 4 weeks apart before progression where confirmation required or 1 determination of CR prior to progression where confirmation not required. PR = at least 2 determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) where confirmation required or 1 determination of PR prior to progression where confirmation not required. RECIST criteria is a set of published rules that define when tumors in cancer patients improve (respond), stay the same (stabilize), or worsen (progress) during treatment. | 61 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: Serum Pharmacokinetic (PK) Parameter AUCs (AUC0-336h (Cycle 1 Only), AUCinf, AUClast AUCtau) | AUC0-336h is the AUC from time zero to 336 hour post dose of a measurable concentration sampling time. AUClast: The AUC from time zero to the last measurable concentration sampling time (tlast) (mass x time x volume-1). AUCinf: The AUC from time zero to infinity (mass x time x volume-1). AUCtau: The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x time x volume-1). | Predose, 1hour (h), 24h, 48h, 72h, 168h, 240h, 336h post dose (cycle 1 & 3) | 
| Phase I: Serum Pharmacokinetic (PK) Parameter Cmax | The maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after single dose administration (mass x volume-1) | Predose, 1hour (h), 24h, 48h, 72h, 168h, 240h, 336h post dose (Cycle 1 & 3) | 
| Phase I: Serum Pharmacokinetic (PK) Parameter Tmax | The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after single dose administration (time) | Predose, 1hour (h), 24h, 48h, 72h, 168h, 240h, 336h post dose (cycle 1 & 3) | 
| Phase ll: Serum Pharmacokinetic (PK) Parameter AUCs (AUC336h, AUCinf, AUClast, AUCtau) | AUC0-336h is the AUC from time zero to 336 hour post dose of a measurable concentration sampling time. AUClast: The AUC from time zero to the last measurable concentration sampling time (tlast) (mass x time x volume-1). AUCinf: The AUC from time zero to infinity (mass x time x volume-1). AUCtau: The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x time x volume-1). | Predose, 1hour (h), 24h, 48h, 72h, 168h, 240h, 336h post dose (cycle 1 & 3) | 
| Phase ll: Serum Pharmacokinetic (PK) Parameter Cmax | The maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after single dose administration (mass x volume-1) | Predose, 1hour (h), 24h, 48h, 72h, 168h, 240h, 336h post dose (Cycle 1 & 3) | 
| Phase ll: Serum Pharmacokinetic (PK) Parameter Tmax | The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after single dose administration (time) | Predose, 1hour (h), 24h, 48h, 72h, 168h, 240h, 336h post dose (Cycle 1 & 3) | 
| Phase I: Presence and/or Concentration of Anti-PDR001 | Assessed PDR001 anti-drug anti-body (ADA) incidence in Phase I patients - the emergence of anti-PDR001 antibodies following one or more intravenous (i.v.) infusions of PDR001. Each cycle = 28 days; End of treatment was expected to be on average 1 year after the start of study treatment. | 42 months | 
| Phase II: Presence and/or Concentration of Anti-PDR001 | Assessed PDR001 anti-drug anti-body (ADA) incidence in Phase I patients - the emergence of anti-PDR001 antibodies following one or more intravenous (i.v.) infusions of PDR001. Each cycle = 28 days; End of treatment was expected to be on average 1 year after the start of study treatment. For Treatment -induced ADA-positive, Percentage was based on subjects ADA-negative at baseline. For Treatment-boosted ADA-positive, Percentage was based on subjects ADA-positive at baseline. | 42 months | 
| Phase l: Overall Response Rate (ORR) as Per Investigator Based on RECIST v1.1 | ORR is the percentage of participants with a best overall response of complete response CR or partial response PR as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 CR = at least two determinations of CR at least 4 weeks apart before progression where confirmation required or one determination of CR prior to progression where confirmation not required. PR = at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) where confirmation required or one determination of PR prior to progression where confirmation not required. RECIST criteria is a set of published rules that define when tumors in cancer patients improve (respond), stay the same (stabilize), or worsen (progress) during treatment. | 27 months | 
| Phase l: Disease Control Rate (DCR) as Per Investigator Based on RECIST v1.1 | DCR is the percentage of patients with a best overall response of CR or PR or stable disease (SD). CR = at least two determinations of CR at least 4 weeks apart before progression where confirmation required or one determination of CR prior to progression where confirmation not required PR = at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) where confirmation required or one determination of PR prior to progression where confirmation not required. SD = at least one SD assessment (or better) > 6 weeks after randomization/start of treatment (and not qualifying for CR or PR). RECIST criteria is a set of published rules that define when tumors in cancer patients improve (respond), stay the same (stabilize), or worsen (progress) during treatment. | 27 months | 
| Phase l: Progression Free Survival (PFS) as Per RECIST v1.1 | PFS is the time from date of start of treatment to the date of event defined as the first documented progression or death due to any cause. PFS is per Kaplan-Meier estimates. RECIST criteria, published in February 2000 by an international collaboration including the European Organization for Research and Treatment of Cancer (EORTC), National Cancer Institute of the United States, and the National Cancer Institute of Canada Clinical Trials Group, is a Response evaluation criteria in solid tumors is a set of published rules that define when tumors in cancer patients improve (respond), stay the same (stabilize), or worsen (progress) during treatment. RECIST criteria is a set of published rules that define when tumors in cancer patients improve (respond), stay the same (stabilize), or worsen (progress) during treatment. | 27 months | 
| Phase I: Duration of Response (DOR) as Per RECIST v1.1 | DOR is measured from the time measurement criteria are met for CR or PR (whichever status is recorded first) until the first date that recurrence or PD is objectively documented. CR = at least 2 determinations of CR at least 4 weeks apart before progression where confirmation required or 1 determination of CR prior to progression where confirmation not required; PR = at least 2 determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) where confirmation required or 1 determination of PR prior to progression where confirmation not required; PD =progression <= 12 weeks after randomization/start of treatment (and not qualifying for CR, PR or SD). SD = at least 1 SD assessment (or better) > 6 weeks after randomization/start of treatment (and not qualifying for CR or PR). RECIST criteria is a set of published rules that define when tumors in cancer patients improve (respond), stay the same (stabilize), or worsen (progress) during treatment | 27 months | 
| Phase l Only: Overall Response Rate (ORR) as Per Investigator Based on Immune Related Response Criteria (irRC) | ORR is the percentage of participants with a best overall response of complete response (CR) or partial response (PR) as per irRC. CR = at least two determinations of CR at least 4 weeks apart before progression where confirmation required or one determination of CR prior to progression where confirmation not required. PR = at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) where confirmation required or one determination of PR prior to progression where confirmation not required. The immune-related response criteria (irRC) is a set of published rules that define when tumors in cancer patients improve (respond), stay the same (stabilize), or worsen (progress) during treatment, where the compound being evaluated is an immuno-oncology drug. | 27 months | 
| Phase l Only: Disease Control Rate (DCR) as Per Investigator Based on irRC | DCR is the percentage of patients with a best overall response of CR or PR or stable disease (SD). CR = at least two determinations of CR at least 4 weeks apart before progression where confirmation required or one determination of CR prior to progression where confirmation not required PR = at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) where confirmation required or one determination of PR prior to progression where confirmation not required. SD = at least one SD assessment (or better) > 6 weeks after randomization/start of treatment (and not qualifying for CR or PR). The immune-related response criteria (irRC) is a set of published rules that define when tumors in cancer patients improve (respond), stay the same (stabilize), or worsen (progress) during treatment, where the compound being evaluated is an immuno-oncology drug. | 27 months | 
| Phase l Only: Progression Free Survival (PFS) as Per irRC | PFS is the time from date of start of treatment to the date of event defined as the first documented progression or death due to any cause. PFS is per Kaplan-Meier estimates. The immune-related response criteria (irRC) is a set of published rules that define when tumors in cancer patients improve (respond), stay the same (stabilize), or worsen (progress) during treatment, where the compound being evaluated is an immuno-oncology drug. | 27 months | 
| Phase I: Duration of Response (DOR) as Per irRC | DOR: measured from time measurement criteria are met for CR or PR (whichever status is recorded first) until first date that recurrence or PD is objectively documented CR: at least 2 determinations of CR at least 4 weeks apart before progression where confirmation required or 1 determination of CR prior to progression where confirmation not required PR: at least 1 determination of PR or better at least 4 weeks apart before progression (& not qualifying for a CR) where confirmation required or 1 determination of PR prior to progression where confirmation not required PD: progression <= start of treatment (& not qualifying for CR, PR or SD) SD: at least 1 SD assessment (or better) > 6 weeks after randomization/start of treatment (& not qualifying for CR or PR) irRC is a set of published rules that define when tumors in cancer patients improve (respond), stay the same (stabilize), or worsen (progress) during treatment, where the compound being evaluated is an immuno-oncology drug | 61 Days | 
| Phase II: Disease Control Rate (DCR) as Per Investigator Based on RECIST v1.1 | DCR is the percentage of patients with a best overall response of CR or PR or stable disease (SD). CR = at least two determinations of CR at least 4 weeks apart before progression where confirmation required or one determination of CR prior to progression where confirmation not required PR = at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) where confirmation required or one determination of PR prior to progression where confirmation not required. SD = at least one SD assessment (or better) > 6 weeks after randomization/start of treatment (and not qualifying for CR or PR). RECIST criteria is a set of published rules that define when tumors in cancer patients improve (respond), stay the same (stabilize), or worsen (progress) during treatment. | 61 months | 
| Phase II: Progression Free Survival as Per Investigator Based on RECIST v1.1 | PFS is the time from date of start of treatment to the date of event defined as the first documented progression or death due to any cause. PFS is per Kaplan-Meier estimates. RECIST criteria, published in February 2000 by an international collaboration including the European Organization for Research and Treatment of Cancer (EORTC), National Cancer Institute of the United States, and the National Cancer Institute of Canada Clinical Trials Group, is a Response evaluation criteria in solid tumors is a set of published rules that define when tumors in cancer patients improve (respond), stay the same (stabilize), or worsen (progress) during treatment. | 61 months | 
| Phase II: Duration of Response (DOR) as Per Investigator Based on RECIST v1.1 | DOR is measured from the time measurement criteria are met for CR or PR (whichever status is recorded first) until the first date that recurrence or PD is objectively documented. CR = at least two determinations of CR at least 4 weeks apart before progression where confirmation required or one determination of CR prior to progression where confirmation not required PR = at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) where confirmation required or one determination of PR prior to progression where confirmation not required. PD = progression <= start of treatment (and not qualifying for CR, PR or SD). SD = at least one SD assessment (or better) > 6 weeks after randomization/start of treatment (and not qualifying for CR or PR). RECIST criteria is a set of published rules that define when tumors in cancer patients improve (respond), stay the same (stabilize), or worsen (progress) during treatment. | 61 months | 
| Phase II: Overall Response Rate (ORR) as Per Investigator Based on irRC | ORR is the percentage of participants with a best overall response CR or PR as per irRC. CR = at least two determinations of CR at least 4 weeks apart before progression where confirmation required or one determination of CR prior to progression where confirmation not required. PR = at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) where confirmation required or one determination of PR prior to progression where confirmation not required. The immune-related response criteria (irRC) is a set of published rules that define when tumors in cancer patients improve (respond), stay the same (stabilize), or worsen (progress) during treatment, where the compound being evaluated is an immuno-oncology drug. | 61 months | 
| Phase II: Disease Control Rate (DCR) as Per Investigator Based on irRC | DCR is the percentage of patients with a best overall response of CR or PR or stable disease (SD). CR = at least two determinations of CR at least 4 weeks apart before progression where confirmation required or one determination of CR prior to progression where confirmation not required PR = at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) where confirmation required or one determination of PR prior to progression where confirmation not required. SD = at least one SD assessment (or better) > 6 weeks after randomization/start of treatment (and not qualifying for CR or PR). The immune-related response criteria (irRC) is a set of published rules that define when tumors in cancer patients improve (respond), stay the same (stabilize), or worsen (progress) during treatment, where the compound being evaluated is an immuno-oncology drug. | 61 months | 
| Phase II: Progression Free Survival (PFS) Per irRC | PFS is the time from date of start of treatment to the date of event defined as the first documented progression or death due to any cause. PFS is per Kaplan-Meier estimates. The immune-related response criteria (irRC) is a set of published rules that define when tumors in cancer patients improve (respond), stay the same (stabilize), or worsen (progress) during treatment, where the compound being evaluated is an immuno-oncology drug. | 61 months | 
| Phase II: Duration of Response (DOR) Per irRC | DOR: measured from time measurement criteria are met for CR or PR (whichever status is recorded first) until first date that recurrence or PD is objectively documented CR: at least 2 determinations of CR at least 4 weeks apart before progression where confirmation required or 1 determination of CR prior to progression where confirmation not required PR: at least 1 determination of PR or better at least 4 weeks apart before progression (& not qualifying for a CR) where confirmation required or 1 determination of PR prior to progression where confirmation not required PD: progression <= start of treatment (& not qualifying for CR, PR or SD) SD: at least 1 SD assessment (or better) > 6 weeks after randomization/start of treatment (& not qualifying for CR or PR) irRC is a set of published rules that define when tumors in cancer patients improve (respond), stay the same (stabilize), or worsen (progress) during treatment, where the compound being evaluated is an immuno-oncology drug | 61 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase I/II, Checkpoint inhibitor, PD-1, PD-L1, NSCLC, PDR001