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Avelumab In Patients With Previously Treated Advanced Stage Classical Hodgkin's Lymphoma (JAVELIN HODGKINS)

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ClinicalTrials.gov Identifier: NCT02603419
Recruitment Status : Active, not recruiting
First Posted : November 11, 2015
Last Update Posted : August 3, 2018
Sponsor:
Information provided by (Responsible Party):
Pfizer

Brief Summary:
This is a Phase 1b, open-label, multi-center study comprising a lead-in phase and an expansion phase. The lead-in phase is a multiple-dose, randomized, parallel-arm, pharmacokinetic and pharmacodynamic study of avelumab as a single agent in adult patients with cHL. Patients enrolled in the lead-in phase of this study are required to have relapsed following a prior autologous or allogeneic HSCT, or to be ineligible for HSCT. Based on the preliminary TO, safety, and efficacy results from the lead-in phase, the expansion phase will evaluate the anti-tumor activity and safety of single-agent avelumab utilizing an intra-patient dose escalation paradigm based on two of the dosing regimens studied in the lead-in phase in 40 cHL patients in whom an allogeneic HSCT has failed.

Condition or disease Intervention/treatment Phase
Hodgkins Lymphoma Drug: Avelumab Phase 1

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 33 participants
Allocation: Randomized
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Pharmacokinetic-pharmacodynamic Study Of Avelumab (msb0010718c) In Patients With Previously Treated Advanced Stage Classical Hodgkin's Lymphoma
Actual Study Start Date : March 10, 2016
Estimated Primary Completion Date : August 20, 2020
Estimated Study Completion Date : August 20, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Avelumab

Arm Intervention/treatment
Experimental: Lead-in phase-Cohort A
X1 mg IV every 2 weeks
Drug: Avelumab
Anti-PD-L1 antibody at X1 mg IV every 2 weeks to optimize dosing for expansion. Treatment with avelumab will continue until disease progression.

Experimental: Lead-in phase-Cohort B
X2 mg IV every 2 weeks
Drug: Avelumab
Anti-PD-L1 antibody at X2 mg IV every 2 weeks to optimize dosing for expansion. Treatment with avelumab will continue until disease progression.

Experimental: Lead-in phase-Cohort C
X3 mg IV every 3 weeks
Drug: Avelumab
Anti-PD-L1 antibody at X3 mg IV every 3 weeks to optimize dosing for expansion. Treatment with avelumab will continue until disease progression

Experimental: Lead-in phase-Cohort D
X4 mg IV every 2 weeks
Drug: Avelumab
Anti-PD-L1 antibody at X3 mg IV every 2 weeks to optimize dosing for expansion. Treatment with avelumab will continue until disease progression

Experimental: Lead-in phase-Cohort E
X5 mg IV every 2 weeks
Drug: Avelumab
Anti-PD-L1 antibody at X mg IV every 2 weeks. Treatment with avelumab will continue until disease progression

Experimental: Expansion phase
X1 mg IV every 2 weeks followed by X1 or X4 mg every 2 weeks
Drug: Avelumab
Anti-PD-L1 antibody at X1 mg IV every 2 weeks which can be escalated to X4 mg every 2 weeks based on safety and efficacy. Treatment with avelumab will continue until disease progression.




Primary Outcome Measures :
  1. Lead-in phase: Percent Receptor Occupancy (TO) [ Time Frame: Days 1, 2, 7, and 14 of cycles 1 and 2, Day 1 (predose) of Cycles 3 and 4 and at End of Treatment. (Cycle = either 14 or 21 days) ]
    Percent TO by dose/schedule in peripheral blood CD14+ monocytes and CD3+ T cells.

  2. Lead-in phase: Maximum Observed Plasma Concentration (Cmax) of avelumab [ Time Frame: Hour 0 (pre-dose), 1, 6, 24 (Day 2), 144 (Day 7), and 312 (Day 14) hours post dose of cycles 1 and 2. Pre-dose on Day 1 of Cycles 3, 4, 6, 8 and every 12 weeks, up to Cycle 20. (Cycle = either 14 or 21 days) ]
    Cmax defined as the maximum plasma concentration of avelumab (MSB0010718C)

  3. Lead-in phase: Area Under the Curve (AUC) of avelumab [ Time Frame: Hour 0 (pre-dose), 1, 6, 24 (Day 2), 48 (Day 3), 144 (Day 7), and 312 (Day 14) hours post dose of Cycles 1 and 2. Pre-dose on Day 1 of Cycles 3, 4, 6, 8 and every 12 weeks, up to Cycle 20. (Cycle = either 14 or 21 days) ]
    AUC defined as the Area Under the Curve during the dosing interval of avelumab (MSB0010718C)

  4. Expansion phase: Objective response [ Time Frame: From treatment start until progressive disease or death due to any cause ]
    Number of participants with objectiver response (CR or PR) as evaluated by the blinded independent central review (BICR)


Secondary Outcome Measures :
  1. Lead-in phase: Anti-Drug Antibody (ADA) levels of avelumab (MSB0010718C) [ Time Frame: Day 1 (pre-dose) of Cycles 1, 2, 3, 4, 6, and 8 and every 12 weeks, up to Cycle 20 (Cycle = either 14 or 21 days) ]
    Immunogenicity assessment of avelumab (MSB0010718C).

  2. Lead-in phase: Phenotype of tumor infiltrating lymphocytes (TILs) in tumor biopsy [ Time Frame: Pre-treatment tumor biopsy (or archival FFPE) for baseline and on-treatment biopsy at Day 28 ]
    Phenotype, quantity, and localization of TILs in tumor biopsy tissue by immunohistochemistry.

  3. Lead-in phase: Gene expression of transcripts associated with immune activation and regulation [ Time Frame: Pre-treatment tumor biopsy (or archival FFPE) for baseline and on-treatment biopsy at Day 28 ]
    Relative expression of transcripts associated with immune activation and regulation in tumor biopsy tissue by gene expression profiling

  4. Lead-in phase: T cell immunophenotype [ Time Frame: Day 1 (pre dose) of Cycle 1; and Day 1 of Cycles 2, 3, 4, 7, 10 and at End of Treatment (Cycle = either 14 or 21 days) ]
    Phenotype, relative proportions, activation state and PD-L1 expression of peripheral blood T cell subsets.

  5. Lead-in phase/Expansion phase: Objective Response (OR) [ Time Frame: From randomization/treatment start until disease progression or death due to any cause ]
    Number of participants with objective response (CR or PR) by Investigator's assessment.

  6. Lead-in phase/Expansion phase: Time to Tumor Response (TTR) [ Time Frame: From the date of randomization/treatment start to the first documentation of objective response (CR or PR) ]
  7. Lead-in phase/Expansion phase: Duration of Response (DR) [ Time Frame: From first documentation of objective response (CR or PR) to the date of first documentation of objective progression of disease (PD) or death due to any cause ]
  8. Lead-in phase/Expansion phase: Progression Free Survival (PFS) [ Time Frame: PFS is defined as the time from randomization/treatment start to the date of the first documentation of objective Progressive Disease (PD) or death due to any cause, whichever occurs first ]
  9. Lead-in phase/Expansion phase: Disease control [ Time Frame: From randomization/treatment start to PD, death or start of new anti-cancer therapy ]
  10. Lead-in phase/Expansion phase: Laboratory abnormalities [ Time Frame: From screening up to 90 days after the last administration of the study drug ]
    As characterized by type, severity (as graded by NCI CTCAE v 4.03) and timing.

  11. Lead-in/Expansion phase: Adverse Events and laboratory abnormalities [ Time Frame: From randomization/treatment start to 90 days after the last administration of the study drug ]
    As graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v.4.03

  12. Expansion phase: Acute and Chronic GVHD [ Time Frame: From treatment start up to 90 days after the last administratio of the study drug ]
    Acute GVHD as defined by the modified Seattle Glucksberg criteria and chronic GVHD, as defined by the NIH Consensus Development Project

  13. Expansion phase: Anti-Drug Antibody (ADA) levels against avelumab [ Time Frame: Day 1 (pre-dose) of Cycles 1, 2, 3, 4, 7 and 13 and at the end of Treatment/Withdrawal ]
    Immunogenicity assessment of avelumab

  14. Expansion phase: Phenotype of tumor infiltrating lymphocytes (TILs) in tumor biopsy [ Time Frame: Pre-treatment tumor biopsy (or archival FFPE) for baseline and on-treatment biopsy at Day 7 of Cycle 3 ]
    Phenotype, quantity, and localization of TILs in tumor biopsy tissue by immunohistochemistry.

  15. Expansion phase: Maximum Observed Plasma Concentration (Cmax) of avelumab [ Time Frame: Hour 0 (pre-dose) and 1 hour post-dose on Day 1 of Cycles 1, 2 and 3. 144 hours post-dose (Day 7) of Cycles 1 and 2. Hour 0 (pre-dose) on Day 1 of Cycles 4,7 and 13. ]
    Cmax is defined as the maximum plasma concentration of avelumab

  16. Expansion phase: Area under the curve (AUC) of avelumab [ Time Frame: Hour 0 (pre-dose) and 1 hour post-dose on Day 1 of Cycles 1, 2 and 3. 144 hours post-dose (Day 7) of Cycles 1 and 2. Hour 0 (pre-dose) on Day 1 of Cycles 4,7 and 13. ]
    AUC is defined as the area the curve during the dosing interval.



Information from the National Library of Medicine

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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

KEY INCLUSION CRITERIA

  • Histological confirmation of classical Hodgkin's Lymphoma (cHL) with relapsed or refractory disease who, for the lead-in phase, either have had a prior autologous or allogeneic HSCT or are not eligible for HSCT, and , for the expansion phase, have had a prior allogeneic HSCT. In the expansion phase there must be a documented CD3+ donor chimerism of ≥20%.
  • Patients must be off previous cHL therapy for at least 28 days prior to randomization in the lead-in phase/first dose of study treatment in the expansion phase.
  • At least 1 fluorodeoxyglucose (FDG) PET avid (Deauville 4/5) measurable lesion >1.5 cm on PET-CT scan as defined by the Response Criteria for Malignant Lymphoma (for the lead-in phase) and the Lugano Classification (for the expansion phase) that has not previously been irradiated.
  • Expansion phase: Required "de novo" or "archival" tumor biopsy, as well as required on treatment biopsy
  • Estern Cooperative Oncology Group (ECOG) Performance Status 0 or 1

KEY EXCLUSION CRITERIA

  • Patients with prior allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) who have had:

    1. Lead-in phase: allo HSCT performed <12 months prior to randomization. Expansion phase: allo-HSCT performed ≤4 months prior to the first dose of study treatment. NOTE: Patients who have had allo-HSCT performed >4 months prior to the first dose of study treatment must have discontinued all immunosuppressive therapy, and must have no clinical evidence of GVHD; or
    2. Immunosuppressive treatment for acute or chronic GVHD within 3 months prior to randomization for the lead-in phase or prior to the first dose of study treatment for the expansion phase (with the exception of those patients who required 15 mg/day oral prednisone or equivalent). Patients who required 15 mg/day oral prednisone or equivalent must have discontinued it within 7 days prior to first dose of study treatment; or
    3. Acute Grade 3 or Grade 4 GVHD at any time in the past (as defined by the modified Seattle Glucksberg criteria (Consensus Conference on Acute GVHD Grading Criteria); or
    4. Prior chronic GVHD (as defined by the NIH Consensus Development Project) that persisted for >6 months and required systemic immunosuppression (with the exception of those patients who required 15 mg/day oral prednisone or equivalent). Patients who required 15 mg/day oral prednisone or equivalent must have discontinued it within 7 days prior to the first dose of study treatment; or
    5. A donor lymphocyte infusion (DLI) within 3 months prior to randomization for the lead-in phase or first dose of study treatment for the expansion phase.
  • Prior therapy with an anti PD 1 or anti PD L1 mAb.

    1. Lead-in Phase: May be enrolled if patient stopped prior anti PD1 or anti-PD-L1 therapy more than one year prior to randomization and had a documented prior response.
    2. Expansion Phase: Prior therapy with an anti-PD-1 or anti-PD-L1 agent following allo-HSCT is prohibited unless the therapy was stopped more than one year prior to the first dose of study treatment, and the patient had a documented prior response. NOTE: Prior therapy with an anti-PD-1 or anti-PD-L1 agent prior to allo-HSCT is permitted with no time limits and irrespective of a documented response.
    3. Patients with a history of ≥Grade 3 anti-PD-1 or anti-PD-L1-related immune toxicity are not eligible.

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): NCT02603419


Locations
United States, California
City of Hope
Duarte, California, United States, 91010
Italy
Az. Ospedaliera-Univers. di Bologna Policlinico S.Orsola-Malpighi
Bologna, BO, Italy, 40138
Istituto Clinico Humanitas U.O. Oncologia ed Ematologia
Rozzano, Milano, Italy, 20089
United Kingdom
Oxford University Hospitals NHS Foundation Trust
Headington, United Kingdom, OX3 7LE
Leeds Teaching Hospital NHS Trust
Leeds, United Kingdom, LS9 7TF
University Hospitals of Leicester NHS Trust
Leicester, United Kingdom, LE1 5WW
University Hospitals of Leicester NHS Trust
Leicester, United Kingdom, LE2 7LG
University College London Hospitals NHS Foundation Trust
London, United Kingdom, N7 9NH
University College Hospital
London, United Kingdom, NW1 2BU
The Christie NHS Foundation Trust
Manchester, United Kingdom, M20 4BX
Plymouth Hospitals NHS Trust, Derriford Hospital
Plymouth, United Kingdom, PL6 8DH
Sponsors and Collaborators
Pfizer
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer

Additional Information:
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT02603419     History of Changes
Other Study ID Numbers: B9991007
2015-002636-41 ( EudraCT Number )
JAVELIN HODGKINS ( Other Identifier: Alias Study Number )
JAVELIN HODGKIN'S ( Other Identifier: Alias Study Number )
First Posted: November 11, 2015    Key Record Dates
Last Update Posted: August 3, 2018
Last Verified: August 2018

Keywords provided by Pfizer:
classical Hodgkins Lymphoma (relapsed/refractory)
post-allogeneic HSCT
anti PD-L1
Phase 1
PK
Receptor occupancy
Immunophenotypic biomarkers

Additional relevant MeSH terms:
Lymphoma
Hodgkin Disease
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs