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

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ClinicalTrials.gov Identifier: NCT02890069
Recruitment Status : Recruiting
First Posted : September 7, 2016
Last Update Posted : April 10, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
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 or disease Intervention/treatment Phase
Colorectal Cancer, Non-small Cell Lung Carcinoma (Adenocarcinoma), Triple Negative Breast Cancer, Renal Cell Carcinoma Biological: PDR001 Drug: LCL161 Drug: Everolimus Drug: Panobinostat Drug: QBM076 Drug: HDM201 Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 400 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : October 14, 2016
Estimated Primary Completion Date : November 15, 2019
Estimated Study Completion Date : December 19, 2019


Arm Intervention/treatment
Experimental: CRC - PDR001 + LCL161
Dose escalation completed; expansion arm.
Biological: PDR001
anti-PD1 antibody

Drug: LCL161
Experimental: NSCLC - PDR001 + LCL161
Dose escalation completed, expansion arm.
Biological: PDR001
anti-PD1 antibody

Drug: LCL161
Experimental: TNBC - PDR001 + LCL161
Dose escalation completed, expansion arm.
Biological: PDR001
anti-PD1 antibody

Drug: LCL161
Experimental: CRC - PDR001+ Everolimus
Dose escalation completed, expansion arm.
Biological: PDR001
anti-PD1 antibody

Drug: Everolimus
Other Name: RAD001

Experimental: NSCLC - PDR001+ Everolimus
Dose escalation completed, expansion arm.
Biological: PDR001
anti-PD1 antibody

Drug: Everolimus
Other Name: RAD001

Experimental: TNBC - PDR001+ Everolimus
Dose escalation completed, expansion arm.
Biological: PDR001
anti-PD1 antibody

Drug: Everolimus
Other Name: RAD001

Experimental: CRC - PDR001 + Panobinostat
Enrollment to this combination arm is closed to further enrollment.
Biological: PDR001
anti-PD1 antibody

Drug: Panobinostat
Other Name: LBH589

Experimental: NSCLC - PDR001 + Panobinostat
Enrollment to this combination arm is closed to further enrollment.
Biological: PDR001
anti-PD1 antibody

Drug: Panobinostat
Other Name: LBH589

Experimental: TNBC - PDR001 + Panobinostat
Enrollment to this combination arm is closed to further enrollment.
Biological: PDR001
anti-PD1 antibody

Drug: Panobinostat
Other Name: LBH589

Experimental: CRC - PDR001 + QBM076
Dose escalation.
Drug: QBM076
Experimental: TNBC - PDR001 + QBM076
Dose escalation.
Drug: QBM076
Experimental: NSCLC- PDR001 + QBM076
Dose escalation.
Drug: QBM076
Experimental: CRC - PDR001 + HDM201
Dose escalation.
Drug: HDM201
Experimental: RCC - PDR001 + HDM201
Dose escalation.
Drug: HDM201



Primary Outcome Measures :
  1. Phase 1: Incidence of dose limiting toxicities (DLTs) [ Time Frame: During the first two cycles ]
    cycle = 28 days

  2. Frequency of dose interruptions and reductions [ Time Frame: Through study completion, an average of 6 months ]
  3. Frequency and severity of treatment-emergent adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: Through study completion, an average of 6 months ]
  4. Changes between baseline and post-baseline laboratory parameters and vital signs [ Time Frame: Through study completion, an average of 6 months ]
  5. Dose intensities [ Time Frame: Through study completion, an average of 6 months ]

Secondary Outcome Measures :
  1. 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) ]
    cycle = 28 days

  2. 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 ]
  3. 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 ]
    cycle = 28 days T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2

  4. 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 ]
    T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2

  5. Presence of anti-PDR001 antibodies [ Time Frame: Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2

  6. 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 ]
    cycle = 28 days T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2

  7. 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 ]
    cycle = 28 days T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2

  8. 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 ]
    T1: treatment period 1 (6 cycles of treatment)

  9. 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 ]
    T1: treatment period 1 (6 cycles of treatment)

  10. 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 ]
    T1: treatment period 1 (6 cycles of treatment)

  11. Concentration of anti-PDR001 antibodies [ Time Frame: Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2

  12. 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) ]
    Cycle = 28 days

  13. 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) ]
    cycle = 28 days

  14. 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 ]
    T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2

  15. 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 ]
    T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2

  16. 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 ]
    cycle = 28 days T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2

  17. 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 ]
    T1: treatment period 1 (6 cycles of treatment)

  18. Time to reach max concentration (Tmax) for LCL161 [ Time Frame: Cycle 1 through cycle 6 in treatment period 1, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment)

  19. Time to reach max concentration (Tmax) for Everolimus [ Time Frame: Cycle 1 through cycle 6 in treatment period 1, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment)

  20. Time to reach max concentration (Tmax) for Panobinostat [ Time Frame: Cycle 1 through cycle 6 in treatment period 1, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment)

  21. 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 ]
    T1: treatment period 1 (6 cycles of treatment)

  22. 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 ]
    T1: treatment period 1 (6 cycles of treatment)

  23. 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 ]
    T1: treatment period 1 (6 cycles of treatment)

  24. 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 ]
    T1: treatment period 1 (6 cycles of treatment)

  25. Time to reach max concentration (Tmax) for QBM076 [ Time Frame: Cycle 1 through cycle 6 in treatment period 1, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment)

  26. Time to reach max concentration (Tmax) for HDM201 [ Time Frame: Cycle 1 through cycle 6 in treatment period 1, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment)

  27. 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 ]
    T1: treatment period 1 (6 cycles of treatment)

  28. 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 ]
    T1: treatment period 1 (6 cycles of treatment)



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

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 </= 3 weeks prior to first dose

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.


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): NCT02890069


Contacts
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Contact: Novartis Pharmaceuticals 1-888-669-6682 Novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111

  Show 25 Study Locations
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals

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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02890069     History of Changes
Other Study ID Numbers: CPDR001X2102
First Posted: September 7, 2016    Key Record Dates
Last Update Posted: April 10, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):
PDR001
CRC
TNBC
NSCLC
RCC
Immunomodulation
Biomarkers
Bayesian logistic regression model

Additional relevant MeSH terms:
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Colorectal Neoplasms
Adenocarcinoma
Carcinoma, Renal Cell
Triple Negative Breast Neoplasms
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Kidney Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Urologic Neoplasms
Urogenital Neoplasms
Kidney Diseases
Urologic Diseases
Breast Neoplasms
Breast Diseases
Skin Diseases
Respiratory Tract Neoplasms
Thoracic Neoplasms
Lung Diseases