Clinical Trial - NCT02890069

A Study of PDR001 in Combination With LCL161, Everolimus or Panobinostat

Recruiting

Sponsor: Novartis Pharmaceuticals

Collaborators:

Information provided by (Responsible party): Sponsor

ClinicalTrials.gov Identifier: NCT02890069

Protocol Info

Short Description: Phase Ib of PDR001 in Combination With LCL161, Everolimus or Panobinostat
Long Description: Phase Ib, Open-label, Multi-center Study to Characterize the Safety, Tolerability and Pharmacodynamics (PD) of PDR001 in Combination With LCL161, Everolimus (RAD001) or Panobinostat (LBH589)
MGH Status: Open
Sponsor: Novartis
Disease Program: Breast

Next Steps


If you are interested in this protocol or in other treatment options at Massachusetts General Hospital, please Request a Consultation.




Purpose

The purpose of this study is to combine the PDR001 checkpoint inhibitor with several agents with immunomodulatory activity to identify the doses and schedule for combination therapy and to preliminarily assess the safety, tolerability, pharmacological and clinical activity of these combinations.
Condition Title Intervention Phase
Colorectal Cancer, Non-small Cell Lung Carcinoma (Adenocarcinoma), Triple Negative Breast Cancer, Re PDR001 LCL161 Everolimus Panobinostat QBM076 HDM201 Phase 1
Study Type Interventional
Official Title Phase Ib, Open-label, Multi-center Study to Characterize the Safety, Tolerability and Pharmacodynamics (PD) of PDR001 in Combination With LCL161, Everolimus (RAD001) or Panobinostat (LBH589)

Primary Outcome Measures

Phase 1: Incidence of dose limiting toxicities (DLTs) [Time Frame: During the first two cycles] [Designated as safety issue: ]

Frequency of dose interruptions and reductions [Time Frame: Through study completion, an average of 6 months] [Designated as safety issue: ]

Frequency and severity of treatment-emergent adverse events (AEs) and serious adverse events (SAEs) [Time Frame: Through study completion, an average of 6 months] [Designated as safety issue: ]

Changes between baseline and post-baseline laboratory parameters and vital signs [Time Frame: Through study completion, an average of 6 months] [Designated as safety issue: ]

Dose intensities [Time Frame: Through study completion, an average of 6 months] [Designated as safety issue: ]


Secondary Outcome Measures

Quantification of Tumor Infiltrating Lymphocytes (TILs) by Hematoxylin [Time Frame: Baseline and approximately after 2 cycles of treatment and at disease progression (an average of 6 months)] [Designated as safety issue: ]

Changes from baseline in ECG parameters in patients recieving PDR001 in combination with Panobinostat [Time Frame: Baseline and end of treatment, an average of 6 months] [Designated as safety issue: ]

Best overall response (BOR) [Time Frame: T1: Every 2 cycles until the start of T2; T2: every 2 cycles till cycle 5, and every 3 cycles till the patient progresses or is withdrawn from study, an average of 6 months] [Designated as safety issue: ]

Time to reach max concentration (Tmax) for PDR001 [Time Frame: Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months] [Designated as safety issue: ]

Presence of anti-PDR001 antibodies [Time Frame: Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months] [Designated as safety issue: ]

Progression free survival (PFS) per RECIST v1.1 [Time Frame: T1: Every 2 cycles until the start of T2; T2: every 2 cycles till cycle 5, and every 3 cycles till the patient progresses or is withdrawn from study, an average of 6 months] [Designated as safety issue: ]

Treatment Free Survival (TFS) [Time Frame: T1: Every 2 cycles until the start of T2; T2: every 2 cycles till cycle 5, and every 3 cycles till the patient progresses or is withdrawn from study, an average of 6 months] [Designated as safety issue: ]

Maximum and minimum plasma concentrations of LCL161 (Cmax and Cmin) [Time Frame: Cycle 1 through cycle 6 in treatment period 1, an average of 6 months] [Designated as safety issue: ]

Maximum and minimum Plasma concentrations of everolimus (Cmax and Cmin) [Time Frame: Cycle 1 through cycle 6 in treatment period 1, an average of 6 months] [Designated as safety issue: ]

Maximum and minimum plasma concentrations of panobinostat (Cmax and Cmin) [Time Frame: Cycle 1 through cycle 6 in treatment period 1, an average of 6 months] [Designated as safety issue: ]

Concentration of anti-PDR001 antibodies [Time Frame: Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months] [Designated as safety issue: ]

Characterization of TILs and myeloid cell infiltrate by IHC (such as CD8, FoxP3 and myeloid markers as appropriate) [Time Frame: Baseline and approximately after 2 cycles of treatment and at disease progression (an average of 6 months)] [Designated as safety issue: ]

Quantification of Tumor Infiltrating Lymphocytes (TILs) by eosin (H&E) stain [Time Frame: Baseline and approximately after 2 cycles of treatment and at disease progression (an average of 6 months)] [Designated as safety issue: ]

Maximum and minimum serum concentration of PDR001 (Cmax and Cmin) [Time Frame: Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months] [Designated as safety issue: ]

Area under the concentration-time curve calculated to the last concentration point (AUClast) for PDR001, as applicable [Time Frame: Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months] [Designated as safety issue: ]

Progression free survival (PFS) per irRC [Time Frame: T1: Every 2 cycles until the start of T2; T2: every 2 cycles till cycle 5, and every 3 cycles till the patient progresses or is withdrawn from study, an average of 6 months] [Designated as safety issue: ]

Area under the concentration-time curve calculated to the last concentration point (AUClast) for LCL161, as applicable [Time Frame: Cycle 1 through cycle 6 in treatment period 1, an average of 6 months] [Designated as safety issue: ]

Time to reach max concentration (Tmax) for LCL161 [Time Frame: Cycle 1 through cycle 6 in treatment period 1, an average of 6 months] [Designated as safety issue: ]

Time to reach max concentration (Tmax) for Everolimus [Time Frame: Cycle 1 through cycle 6 in treatment period 1, an average of 6 months] [Designated as safety issue: ]

Time to reach max concentration (Tmax) for Panobinostat [Time Frame: Cycle 1 through cycle 6 in treatment period 1, an average of 6 months] [Designated as safety issue: ]

Area under the concentration-time curve calculated to the last concentration point (AUClast) for Everolimus, as applicable [Time Frame: Cycle 1 through cycle 6 in treatment period 1, an average of 6 months] [Designated as safety issue: ]

Area under the concentration-time curve calculated to the last concentration point (AUClast) for Panobinostat, as applicable [Time Frame: Cycle 1 through cycle 6 in treatment period 1, an average of 6 months] [Designated as safety issue: ]

Maximum and minimum Plasma concentrations of QBM076 (Cmax and Cmin) [Time Frame: Cycle 1 through cycle 6 in treatment period 1, an average of 6 months] [Designated as safety issue: ]

Maximum and minimum Plasma concentrations of HDM201 (Cmax and Cmin) [Time Frame: Cycle 1 through cycle 6 in treatment period 1, an average of 6 months] [Designated as safety issue: ]

Time to reach max concentration (Tmax) for QBM076 [Time Frame: Cycle 1 through cycle 6 in treatment period 1, an average of 6 months] [Designated as safety issue: ]

Time to reach max concentration (Tmax) for HDM201 [Time Frame: Cycle 1 through cycle 6 in treatment period 1, an average of 6 months] [Designated as safety issue: ]

Area under the concentration-time curve calculated to the last concentration point (AUClast) for QBM076, as applicable [Time Frame: Cycle 1 through cycle 6 in treatment period 1, an average of 6 months] [Designated as safety issue: ]

Area under the concentration-time curve calculated to the last concentration point (AUClast) for HDM201, as applicable [Time Frame: Cycle 1 through cycle 6 in treatment period 1, an average of 6 months] [Designated as safety issue: ]

Estimated Enrollment: 400
Study Start Date: October 2016
Estimated Study Completion Date: December 2019
Estimated Primary Completion Date: November 2019
Arms Assigned Interventions

Experimental:CRC - PDR001 + LCL161

Dose escalation completed; expansion arm.
Drug:LCL161

Experimental:NSCLC - PDR001 + LCL161

Dose escalation completed, expansion arm.

Experimental:TNBC - PDR001 + LCL161

Dose escalation completed, expansion arm.

Experimental:CRC - PDR001+ Everolimus

Dose escalation completed, expansion arm.
Drug:Everolimus

Experimental:NSCLC - PDR001+ Everolimus

Dose escalation completed, expansion arm.

Experimental:TNBC - PDR001+ Everolimus

Dose escalation completed, expansion arm.

Experimental:CRC - PDR001 + Panobinostat

Enrollment to this combination arm is closed to further enrollment.
Drug:Panobinostat

Experimental:NSCLC - PDR001 + Panobinostat

Enrollment to this combination arm is closed to further enrollment.

Experimental:TNBC - PDR001 + Panobinostat

Enrollment to this combination arm is closed to further enrollment.

Experimental:CRC - PDR001 + QBM076

Dose escalation.
Drug:QBM076

Experimental:TNBC - PDR001 + QBM076

Dose escalation.

Experimental:NSCLC- PDR001 + QBM076

Dose escalation.

Experimental:CRC - PDR001 + HDM201

Dose escalation.
Drug:HDM201

Experimental:RCC - PDR001 + HDM201

Dose escalation.

Eligibility

Ages Eligible for Study: N/A-N/A

Genders Eligible for Study: All

Accepts Healthly Volunteers: No

Inclusion Criteria:

  • Written informed consent prior to any procedure
  • Patients with advanced/metastatic cancer, with measurable disease as determined by RECIST version 1.1, who have progressed despite standard therapy or are intolerant to SOC, or for whom no standard therapy exists. Patients must fit into one of the following groups:

• CRC •NSCLC • TNBC• RCC

  • ECOG ≤ 2
  • Patient must have a site of disease for biopsy, and be a candidate for tumor biopsy according to the institution's guidelines. Patient must be willing to undergo a new tumor biopsy at screening, and again during therapy on this study.
  • Prior therapy with PD-1/PDL-1 inhibitors is allowed provided any toxicity attributed to prior PD-1- or PD-L1-directed therapy did not lead to discontinuation of therapy.

Exclusion Criteria:

  • Presence of symptomatic central nervous system (CNS) metastases, or CNS metastases that require local CNS-directed therapy within prior 2 weeks.
  • Patients with known hypersensitivity to any of the components of an investigational treatment will be excluded from participation in the corresponding arm but are eligible for participation in other study arm; Patients that have a history of hypersensitivity to rapamycin derivatives will be excluded from participation in the everolimus arm
  • History of or current drug-induced interstitial lung disease or pneumonitis grade ≥2
  • Out of range lab values as defined in protocol
  • Impaired cardiac function or clinically significant cardiac disease
  • Active, known or suspected autoimmune disease
  • Human Immunodeficiency Virus (HIV), or active Hepatitis C (HCV) virus. Escalation: active Hepatitis B (HBV); Expansion: Patients with Chronic HBV currently on medication will not be excluded.
  • Impairment of gastrointestinal (GI) function
  • Malignant disease, other than that being treated in this study
  • Systemic anti-cancer therapy within 2 weeks of the first dose of study treatment. For cytotoxic agents that have major delayed toxicity and washout period is 6 weeks; prior immunotherapy - washout is 4 weeks
  • Active infection requiring systemic antibiotic therapy.
  • Patients requiring chronic treatment with systemic steroid therapy, other than replacement dose steroids or treatment with low, stable dose of steroid (<10 mg/day prednisone or equivalent) for stable CNS metastatic disease.
  • Patients receiving systemic treatment with any immunosuppressive medication.
  • Major surgery within 2 weeks of the first dose of study treatment
  • Radiotherapy within 2 weeks of the first dose of study drug
  • Participation in an interventional, investigational study within 2 weeks of the first dose 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 therapy.
  • Use of hematopoietic colony stimulating growth factors

Additional exclusion criteria for PDR001/LCL161

  • Patients requiring medications metabolized through CYP3A4/5 and have a narrow therapeutic index or medications that are CYP3A4 substrates that cause QT prolongation
  • Patients requiring treatment with strong CYP2C8 inhibitors

Additional exclusion criteria for PDR001/Everolimus

  • Patients requiring treatment with moderate CYP3A4 inhibitors
  • Patients requiring treatment with a strong CYP3A4 inhibitor or inducer

Additional exclusion criteria for PDR001/Panobinostat-

  • Patient who received DAC inhibitors
  • Patient needing valproic acid during the study or within 5 days prior to first dose
  • Patients requiring medications that are sensitive CYP2D6 substrates areCYP2D6 substrates with a narrow therapeutic index or are anti-arrhythmic drugs/drugs with QT-prolongation risks
  • Patients requiring a strong inhibitor or inducer of CYP3A4
  • Clinically significant, uncontrolled heart disease and/or recent cardiac event within 6 months prior to study
  • Unresolved diarrhea ≥ CTCAE grade 2 or a medical condition associated with chronic diarrhea
  • Taking medications with QT prolongation risk or interval or inducing Torsade de pointes

Additional exclusion criteria for PDR001/QBM076-

  • Patients requiring medications that are strong inducers or strong inhibitors of CYP3A4
  • Patients requiring medications with narrow therapeutic index CYP3A4 substrates
  • Women using any form of hormonal contraception (oral, injected, implanted, transdermal) will be excluded (unless they are willing to switch to another effective form of contraception under their physician's guidance)

Additional exclusion criteria for PDR001/HDM201-

  • Prior treatment with compounds with the same mode of action as proposed for HDM201, i.e. an inhibition of the interaction of TP53 with HDM2, e.g. RG7112 or CGM097
  • Patients who require the following treatments moderate to strong CYP3A4 inhibitors; any substrates of CYP3A4/5 with a narrow therapeutic index
  • Moderate to strong CYP3A4 inducers
  • Patients having out of range values for:

Absolute neutrophil count (ANC) <1500/µL; Platelets < 100 000/µL

Other protocol-defined inclusion exclusion criteria may apply.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT02890069

Locations

  • United States, California
    • Novartis Investigative Site Santa Monica, California, United States, 90404
  • United States, Maryland
    • Novartis Investigative Site Baltimore, Maryland, United States, 21231
  • United States, Massachusetts
    • Novartis Investigative Site Boston, Massachusetts, United States, 02114
  • United States, Michigan
    • Novartis Investigative Site Ann Arbor, Michigan, United States, 48109
  • United States, Missouri
    • Novartis Investigative Site Saint Louis, Missouri, United States, 63110
  • United States, Texas
    • Novartis Investigative Site Houston, Texas, United States, 77030
    • Novartis Investigative Site San Antonio, Texas, United States, 78229
  • United States, Utah
    • Novartis Investigative Site Salt Lake City, Utah, United States, 84112
  • United States, Washington
    • Novartis Investigative Site Seattle, Washington, United States, 98105
  • Germany,
    • Novartis Investigative Site Jena, , Germany, 07740
    • Novartis Investigative Site Ulm, , Germany, 89081
    • Novartis Investigative Site Wuerzburg, , Germany, 97080
  • Korea, Republic of, Gyeonggi-do
    • Novartis Investigative Site Seoul, Gyeonggi-do, Korea, Republic of, 110744
  • Korea, Republic of, Korea
    • Novartis Investigative Site Seoul, Korea, Korea, Republic of, 05505
  • Netherlands,
    • Novartis Investigative Site Amsterdam, , Netherlands, 1066 CX
    • Novartis Investigative Site Leiden, , Netherlands, 2300 RC
    • Novartis Investigative Site Rotterdam, , Netherlands, 3075 EA
    • Novartis Investigative Site Utrecht, , Netherlands, 3584CX
  • Spain, Catalunya
    • Novartis Investigative Site Barcelona, Catalunya, Spain, 08035
  • Spain, Navarra
    • Novartis Investigative Site Pamplona, Navarra, Spain, 31008
  • Spain,
    • Novartis Investigative Site Madrid, , Spain, 28041
  • Taiwan,
    • Novartis Investigative Site Taipei, , Taiwan, 10002
  • United Kingdom,
    • Novartis Investigative Site Manchester, , United Kingdom, M20 9BX
    • Novartis Investigative Site Oxford, , United Kingdom, OX3 7LJ
    • Novartis Investigative Site Sutton, , United Kingdom, SM2 5PT

Sponsors and Collaborators

Novartis Pharmaceuticals

More Information

No publications provided

Responsible Party: Sponsor
ClinicalTrials.gov Identifier: NCT02890069
Other Study ID Numbers:
Study First Received:
Last Updated:
Health Authority:

Keywords provided by Novartis:

PDR001

CRC

TNBC

NSCLC

RCC

Immunomodulation

Biomarkers

Bayesian logistic regression model

Additional relevant MeSH terms:

Colorectal Neoplasms

Adenocarcinoma

Carcinoma, Renal Cell

Triple Negative Breast Neoplasms

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Kidney Neoplasms

Everolimus

Sirolimus

Panobinostat

Next Steps


If you are interested in this protocol or in other treatment options at Massachusetts General Hospital, please Request a Consultation.







ClinicalTrials.gov processed this data on August 15, 2019