Clinical trial NCT02144038: Study of the Safety and Effectiveness of LGH447 and BYL719 in Patients With Relapsed and Refractory Multiple Myeloma
Official title: A Phase Ib/II, Multi-center, Study of Oral LGH447 in Combination With Oral BYL719 in Patients With Relapsed and Refractory Multiple Myeloma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Relapsed and Refractory Multiple Myeloma
Keywords: multiple myeloma,
relapsed and refractory,
LGH447,
pan-PIM inhibitor,
PIM Kinase,
BYL719,
PI3K inhibitor
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2014-05-21
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a Phase Ib/II study with the primary purpose of the Phase Ib part being to estimate the MTD and/or recommended phase 2 dose (RP2D) of the combination of LGH447 and BYL719 when administered orally to adult patients with relapsed and refractory multiple myeloma. Once the MTD and/or RP2D is determined for the combination of LGH447 and BYL719, additional patients will be enrolled in the Phase II part to determine whether the combination of LGH447 and BYL719 exhibits improved anti-multiple myeloma activity compared to single agent LGH447. This trial never made it to the Phase II part of the this trial.


Eligibility criteria: Inclusion Criteria:

* Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2
* Patients with a confirmed diagnosis of multiple myeloma who have received two or more lines of therapy and are refractory to their most recent line of therapy, as defined as relapse while on therapy or within 60 days from their last line of therapy. If patient has not received either an immunomodulatory drug (IMID) or proteasome inhibitor as a prior therapy then Investigator must notify Novartis prior to the patient enrollment. Patients who have received a prior bone marrow transplant and otherwise meet the inclusion criteria are eligible for this study
* For patients in the Phase II portion of the study, must have measurable disease defined by at least 1 of the following 3 measurements:

  * Serum M-protein ≥ 0.5 g/dL
  * Urine M-protein ≥ 200 mg/24 hours OR
  * Serum free light chain (FLC) \> 100 mg/L of involved FLC
* All patients must be willing to undergo a mandatory bone marrow aspirate and/or biopsy at baseline for the assessment of biomarker/pharmacodynamics and disease status

Exclusion Criteria:

* Systemic antineoplastic therapy (including unconjugated therapeutic antibodies and toxin immunoconjugates) or any experimental therapy within 14 days or 5 half-lives, whichever is shorter, before the first dose of either study drug
* Radiotherapy within 14 days before the first dose of either study drug except localized radiation therapy for lytic bone lesions and plasmacytomas
* Major surgery within 2 weeks before the first dose of either study drug
* Ongoing therapy with chronic or high dose corticosteroids. Low dose steroids (i.e. prednisone ≤ 10 mg or an equivalent steroid dose), inhaled and topical steroids are permitted
* Patients who are currently receiving treatment with a prohibited medication that cannot be discontinued at least one week prior to the start of treatment:
* Narrow Therapeutic index substrates, strong inhibitors and strong inducers of CYP3A4
* Strong Inhibitors of CYP2D6
* Narrow therapeutic index substrates of CYP2C8, CYP2C9, CYP2C19 and CYP2D6
* Any of the following clinical laboratory results during screening (i.e., within 28 days before the first dose of either study drug):
* Absolute neutrophil count (ANC) \< 1,000/mm3 without growth factor support within 7 days prior to testing
* Platelet count \< 75,000 mm3 without transfusion support within 7 days prior to testing
* Bilirubin \> 1.5 times the upper limit of the normal range (ULN).
* Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 3 times the ULN.
* Calculated creatinine clearance \< 30 ml/min according to Cockcroft-Gault equation
* Corrected QT interval (QTc) of \> 450 milliseconds (ms) in males and \> 470 milliseconds (ms) in females on baseline electrocardiogram (ECG) (using Fridericia \[QTcF\] corrected QT interval

Primary outcomes:
measure: Phase Ib: Number of Total Dose-limiting Toxicities (DLT)
timeFrame: Cycle 1 (28 days)
measure: Phase II: Overall Response Rate (ORR) as assessed by Investigators
timeFrame: 29 months (End of Study)
Secondary outcomes:
measure: Phase II: Percent change of ORR (Overall Response Rate) between the two arms
timeFrame: 29 months (End of Study)
measure: Number of participants with adverse events, serious adverse events, changes in laboratory values, and electrocardiograms (ECGs), as a measure of safety and tolerability.
timeFrame: 23 months
measure: Determine single and multiple dose Pharmacokinetics (PK) profiles
timeFrame: Approximately 8 months
measure: Changes between pre- and post-treatment levels of pS6RP and 4EBP1 levels in bone marrow aspirates and 4EBP1 in peripheral blood
timeFrame: baseline, Cycle 2 Day 1
measure: Phase II: Absolute difference in ORR
timeFrame: 29 months (End of Study)
measure: Disease Control Rate
timeFrame: 29 months (End of Study)
measure: Progression Free Survival
timeFrame: 29 months (End of Study)
measure: Time to response
timeFrame: 29 months (End of Study)
measure: Duration of Response
timeFrame: 29 months (End of Study)
Other outcomes:
Locations:
city: Houston
country: United States
facility: University of Texas/MD Anderson Cancer Center Dept.ofMDAndersonCancerCtr(SC)
state: Texas
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance Oncology Dept
state: Washington
city: Madison
country: United States
facility: University of Wisconsin / Paul P. Carbone Comp Cancer Center Dept of Onc.
state: Wisconsin
city: Prahran
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Heidelberg
country: Germany
facility: Novartis Investigative Site
city: Kiel
country: Germany
facility: Novartis Investigative Site
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Singapore
country: Singapore
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: