Clinical trial NCT02404441: Phase I/II Study of PDR001 in Patients With Advanced Malignancies
Official title: Open Label Multicenter Phase I/II Study of the Safety and Efficacy of PDR001 Administered to Patients With Advanced Malignancies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Melanoma
Non-small Sell Lung Cancer (NSCLC)
Triple Negative Breast Cancer
Anaplastic Thyroid Cancer
Other Solid Tumors
Keywords: Phase I/II
PDR001
Checkpoint inhibitor
PD-1
PD-L1
NSCLC
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2015-03-31
Enrollment: 319
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Phase l: The Exposure (AUC(0-336h)) After First Dose of Treatment at Cycle 3 (Each Cycle = 28 Days)
timeFrame: Predose, 1hour (h), 24h, 48h, 72h, 168h, 240h, 336h post dose (cycle 3)
measure: Phase l: Incidence of Dose Limiting Toxicities (DLTs)
timeFrame: 8 months
measure: Phase ll: Overall Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors (RECIST v1.1)
timeFrame: 61 months
Secondary outcomes:
measure: Phase I: Serum Pharmacokinetic (PK) Parameter AUCs (AUC0-336h (Cycle 1 Only), AUCinf, AUClast AUCtau)
timeFrame: Predose, 1hour (h), 24h, 48h, 72h, 168h, 240h, 336h post dose (cycle 1 & 3)
measure: Phase I: Serum Pharmacokinetic (PK) Parameter Cmax
timeFrame: Predose, 1hour (h), 24h, 48h, 72h, 168h, 240h, 336h post dose (Cycle 1 & 3)
measure: Phase I: Serum Pharmacokinetic (PK) Parameter Tmax
timeFrame: Predose, 1hour (h), 24h, 48h, 72h, 168h, 240h, 336h post dose (cycle 1 & 3)
measure: Phase ll: Serum Pharmacokinetic (PK) Parameter AUCs (AUC336h, AUCinf, AUClast, AUCtau)
timeFrame: Predose, 1hour (h), 24h, 48h, 72h, 168h, 240h, 336h post dose (cycle 1 & 3)
measure: Phase ll: Serum Pharmacokinetic (PK) Parameter Cmax
timeFrame: Predose, 1hour (h), 24h, 48h, 72h, 168h, 240h, 336h post dose (Cycle 1 & 3)
measure: Phase ll: Serum Pharmacokinetic (PK) Parameter Tmax
timeFrame: Predose, 1hour (h), 24h, 48h, 72h, 168h, 240h, 336h post dose (Cycle 1 & 3)
measure: Phase I: Presence and/or Concentration of Anti-PDR001
timeFrame: 42 months
measure: Phase II: Presence and/or Concentration of Anti-PDR001
timeFrame: 42 months
measure: Phase l: Overall Response Rate (ORR) as Per Investigator Based on RECIST v1.1
timeFrame: 27 months
measure: Phase l: Disease Control Rate (DCR) as Per Investigator Based on RECIST v1.1
timeFrame: 27 months
measure: Phase l: Progression Free Survival (PFS) as Per RECIST v1.1
timeFrame: 27 months
measure: Phase I: Duration of Response (DOR) as Per RECIST v1.1
timeFrame: 27 months
measure: Phase l Only: Overall Response Rate (ORR) as Per Investigator Based on Immune Related Response Criteria (irRC)
timeFrame: 27 months
measure: Phase l Only: Disease Control Rate (DCR) as Per Investigator Based on irRC
timeFrame: 27 months
measure: Phase l Only: Progression Free Survival (PFS) as Per irRC
timeFrame: 27 months
measure: Phase I: Duration of Response (DOR) as Per irRC
timeFrame: 61 Days
measure: Phase II: Disease Control Rate (DCR) as Per Investigator Based on RECIST v1.1
timeFrame: 61 months
measure: Phase II: Progression Free Survival as Per Investigator Based on RECIST v1.1
timeFrame: 61 months
measure: Phase II: Duration of Response (DOR) as Per Investigator Based on RECIST v1.1
timeFrame: 61 months
measure: Phase II: Overall Response Rate (ORR) as Per Investigator Based on irRC
timeFrame: 61 months
measure: Phase II: Disease Control Rate (DCR) as Per Investigator Based on irRC
timeFrame: 61 months
measure: Phase II: Progression Free Survival (PFS) Per irRC
timeFrame: 61 months
measure: Phase II: Duration of Response (DOR) Per irRC
timeFrame: 61 months
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: The Sidney Kimmel Cancer Center at Johns Hopkins Hospital Johns Hopkins
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Portland
country: United States
facility: Oregon Health and Science University SC-10
state: Oregon
city: Nashville
country: United States
facility: Sarah Cannon Research Institute SCRI RC
state: Tennessee
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center MD Anderson PSC
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute Univ. of Utah HCI
state: Utah
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Paris Cedex 10
country: France
facility: Novartis Investigative Site
city: Toulouse Cedex 9
country: France
facility: Novartis Investigative Site
city: Villejuif Cedex
country: France
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Jena
country: Germany
facility: Novartis Investigative Site
city: Ulm
country: Germany
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Debrecen
country: Hungary
facility: Novartis Investigative Site
city: Bologna
country: Italy
facility: Novartis Investigative Site
state: BO
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Rozzano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Modena
country: Italy
facility: Novartis Investigative Site
state: MO
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Ashrafieh
country: Lebanon
facility: Novartis Investigative Site
city: Amsterdam
country: Netherlands
facility: Novartis Investigative Site
city: Leiden
country: Netherlands
facility: Novartis Investigative Site
city: Oslo
country: Norway
facility: Novartis Investigative Site
city: Gdansk
country: Poland
facility: Novartis Investigative Site
city: Poznan
country: Poland
facility: Novartis Investigative Site
city: Rzeszow
country: Poland
facility: Novartis Investigative Site
city: Warszawa
country: Poland
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Tainan
country: Taiwan
facility: Novartis Investigative Site
state: Taiwan ROC
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Songkhla
country: Thailand
facility: Novartis Investigative Site
state: Hat Yai
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Adana
country: Turkey
facility: Novartis Investigative Site
city: Edirne
country: Turkey
facility: Novartis Investigative Site
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
city: Izmir
country: Turkey
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Capdevila J, Wirth LJ, Ernst T, Ponce Aix S, Lin CC, Ramlau R, Butler MO, Delord JP, Gelderblom H, Ascierto PA, Fasolo A, Fuhrer D, Hutter-Kronke ML, Forde PM, Wrona A, Santoro A, Sadow PM, Szpakowski S, Wu H, Bostel G, Faris J, Cameron S, Varga A, Taylor M. PD-1 Blockade in Anaplastic Thyroid Carcinoma. J Clin Oncol. 2020 Aug 10;38(23):2620-2627. doi: 10.1200/JCO.19.02727. Epub 2020 May 4.
citation: Naing A, Gainor JF, Gelderblom H, Forde PM, Butler MO, Lin CC, Sharma S, Ochoa de Olza M, Varga A, Taylor M, Schellens JHM, Wu H, Sun H, Silva AP, Faris J, Mataraza J, Cameron S, Bauer TM. A first-in-human phase 1 dose escalation study of spartalizumab (PDR001), an anti-PD-1 antibody, in patients with advanced solid tumors. J Immunother Cancer. 2020 Mar;8(1):e000530. doi: 10.1136/jitc-2020-000530.