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

NCT02404441 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: CPDR001X21012014-003929-17
• Study Type: interventional
• Target: 319
• Locations: 14 countries
• Sites: 41

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.

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

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (23)

• Phase I: Serum Pharmacokinetic (PK) Parameter AUCs (AUC0-336h (Cycle 1 Only), AUCinf, AUClast AUCtau)

  Predose, 1hour (h), 24h, 48h, 72h, 168h, 240h, 336h post dose (cycle 1 & 3)

• Phase I: Serum Pharmacokinetic (PK) Parameter Cmax

  Predose, 1hour (h), 24h, 48h, 72h, 168h, 240h, 336h post dose (Cycle 1 & 3)

• Phase I: Serum Pharmacokinetic (PK) Parameter Tmax

  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)

  Predose, 1hour (h), 24h, 48h, 72h, 168h, 240h, 336h post dose (cycle 1 & 3)

• Phase ll: Serum Pharmacokinetic (PK) Parameter Cmax

  Predose, 1hour (h), 24h, 48h, 72h, 168h, 240h, 336h post dose (Cycle 1 & 3)

Study Arms (2)

patients with solid tumors

OTHER

Phase I Dose escalation cohorts

Biological: PDR001

Selected tumor types

OTHER

Phase II expansion: Selected tumor types: melanoma, NSCLC, triple negative breast cancer, anaplastic thyroid cancer

Biological: PDR001

Interventions

PDR001 BIOLOGICAL

anti-PD1 antibody

Selected tumor types; patients with solid tumors

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (41)

The Sidney Kimmel Cancer Center at Johns Hopkins Hospital Johns Hopkins

Baltimore, Maryland, 21287-0013, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Oregon Health and Science University SC-10

Portland, Oregon, 97239, United States

Location

Sarah Cannon Research Institute SCRI RC

Nashville, Tennessee, 37203, United States

Location

University of Texas MD Anderson Cancer Center MD Anderson PSC

Houston, Texas, 77030, United States

Location

Huntsman Cancer Institute Univ. of Utah HCI

Salt Lake City, Utah, 84112-0550, United States

Location

Novartis Investigative Site

Toronto, Ontario, M5G 1Z6, Canada

Location

Novartis Investigative Site

Paris, 75475, France

Location

Novartis Investigative Site

Toulouse, 31059, France

Location

Novartis Investigative Site

Villejuif, 94800, France

Location

Novartis Investigative Site

Essen, 45147, Germany

Location

Novartis Investigative Site

Jena, 07740, Germany

Location

Novartis Investigative Site

Ulm, 89081, Germany

Location

Novartis Investigative Site

Budapest, 1134, Hungary

Location

Novartis Investigative Site

Debrecen, 4032, Hungary

Location

Novartis Investigative Site

Bologna, BO, 40138, Italy

Location

Novartis Investigative Site

Milan, MI, 20132, Italy

Location

Novartis Investigative Site

Rozzano, MI, 20089, Italy

Location

Novartis Investigative Site

Modena, MO, 41124, Italy

Location

Novartis Investigative Site

Napoli, 80131, Italy

Location

Novartis Investigative Site

El Achrafiyé, 166830, Lebanon

Location

Novartis Investigative Site

Amsterdam, 1066 CX, Netherlands

Location

Novartis Investigative Site

Leiden, 2300 RC, Netherlands

Location

Novartis Investigative Site

Oslo, 0310, Norway

Location

Novartis Investigative Site

Gdansk, 80 952, Poland

Location

Novartis Investigative Site

Poznan, 60-693, Poland

Location

Novartis Investigative Site

Rzeszów, 35-021, Poland

Location

Novartis Investigative Site

Warsaw, 02 781, Poland

Location

Novartis Investigative Site

Barcelona, Catalonia, 08035, Spain

Location

Novartis Investigative Site

Madrid, 28034, Spain

Location

Novartis Investigative Site

Madrid, 28041, Spain

Location

Novartis Investigative Site

Madrid, 28050, Spain

Location

Novartis Investigative Site

Tainan, Taiwan ROC, 70403, Taiwan

Location

Novartis Investigative Site

Taipei, 10002, Taiwan

Location

Novartis Investigative Site

Songkhla, Hat Yai, 90110, Thailand

Location

Novartis Investigative Site

Bangkok, 10330, Thailand

Location

Novartis Investigative Site

Adana, 01250, Turkey (Türkiye)

Location

Novartis Investigative Site

Edirne, 22030, Turkey (Türkiye)

Location

Novartis Investigative Site

Istanbul, 34303, Turkey (Türkiye)

Location

Novartis Investigative Site

Istanbul, 34890, Turkey (Türkiye)

Location

Novartis Investigative Site

Izmir, 35040, Turkey (Türkiye)

Location

Related Publications (2)

• 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.

  PMID: 32364844 DERIVED

• 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.

  PMID: 32179633 DERIVED

MeSH Terms

Conditions

Melanoma; Carcinoma, Non-Small-Cell Lung; Triple Negative Breast Neoplasms; Thyroid Carcinoma, Anaplastic

Interventions

spartalizumab

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases; Breast Neoplasms; Breast Diseases; Carcinoma; Neoplasms, Glandular and Epithelial

Limitations and Caveats

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.

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

novartis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: March 20, 2015
• First Posted: March 31, 2015
• Study Start: April 27, 2015
• Primary Completion: July 21, 2020
• Study Completion: July 21, 2020
• Last Updated: August 3, 2022
• Results First Posted: September 29, 2021

Record last verified: 2022-08

Data Sharing

• IPD Sharing: Will share

Locations

TH (2); LE (1); FR (3); CA (1); DE (3); NL (2); US (6); ES (4); TU (5); HU (2); NO (1); PL (4); TW (2); IT (5)