Study of the Safety and Effectiveness of LGH447 and BYL719 in Patients With Relapsed and Refractory Multiple Myeloma

A Phase Ib/II, Multi-center, Study of Oral LGH447 in Combination With Oral BYL719 in Patients With Relapsed and Refractory Multiple Myeloma

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.

Study Overview

• Status: Completed
• Conditions: Relapsed and Refractory Multiple Myeloma
• Intervention / Treatment: Drug: LGH447; Drug: BYL719

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Prahran, Victoria, Australia, 3181
      • Novartis Investigative Site
• Germany
  • Heidelberg, Germany, 69120
    • Novartis Investigative Site
  • Kiel, Germany, 24105
    • Novartis Investigative Site
• Italy
  • MI
    • Milano, MI, Italy, 20133
      • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 169608
    • Novartis Investigative Site
• United States
  • Texas
    • Houston, Texas, United States, 77030-4009
      • University of Texas/MD Anderson Cancer Center Dept.ofMDAndersonCancerCtr(SC)
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Cancer Care Alliance Oncology Dept
  • Wisconsin
    • Madison, Wisconsin, United States, 53792-6164
      • University of Wisconsin / Paul P. Carbone Comp Cancer Center Dept of Onc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase Ib: LGH447 + BYL719; Dose-escalation, LGH447 in combinatinon with BYL719	Drug: LGH447; pan-PIM inhibitor; Drug: BYL719; PI3K-alpha inhibitor
Experimental: Phase II: LGH447 + BYL719; LGH447 + BYL719 (dosing according to MTD/RP2D from Phase Ib portion of the study)	Drug: LGH447; pan-PIM inhibitor; Drug: BYL719; PI3K-alpha inhibitor
Experimental: Phase II: LGH447 alone; LGH447 alone (dosing according to single-agent RDE)	Drug: LGH447; pan-PIM inhibitor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase Ib: Number of Total Dose-limiting Toxicities (DLT)	Using a Bayesian logistic regression model (BLRM) to guide dose escalation and predict MTD or determine the RP2D for LGH447 in combination with BYL719 in relapsed and refractory multiple myeloma. The frequency and characteristics of DLTs will be assessed.	Cycle 1 (28 days)
Phase II: Overall Response Rate (ORR) as assessed by Investigators	The proportion of patients with a confirmed best overall response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) as assessed by Investigators using the International Myeloma Working group (IMWG) Criteria with modifications. End of Study (defined as the time when all patients have completed at least 6 cycles of treatment or discontinued treatment, or have been lost to follow up, whichever occurs first.	29 months (End of Study)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase II: Percent change of ORR (Overall Response Rate) between the two arms	The ORR percent change between the two arms, LGH447 in combination with BYL719 and LGH447 alone, is the parameter of interest. Both observed and Bayesian estimates of ORR percent change along with 80% confidence intervals and credible intervals will be calculated. End of Study (defined as the time when all patients have completed at least 6 cycles of treatment or discontinued treatment, or have been lost to follow up, whichever occurs first.	29 months (End of Study)
Number of participants with adverse events, serious adverse events, changes in laboratory values, and electrocardiograms (ECGs), as a measure of safety and tolerability.	Assessments consisted of recording all adverse events (AEs) and serious adverse events (SAEs), the regular monitoring of hematology, blood chemistry, urinalysis, and coagulation parameters, as well as electrocardiograms.	23 months
Determine single and multiple dose Pharmacokinetics (PK) profiles	To determine the single and multiple dose PK profiles of the LGH447 and BYL719 combination (Phase Ib and II) and LGH447 alone (Phase II), by measuring plasma concentrations of LGH447 and BYL719 respectively at different timepoints prior and post study drug combination dosing on several days within cycle 1 and subsequent cycles for all patients in the Phase 1b and for the first 15 patients in each arm in the Phase 2 portion of the study. PK parameters including but not limited to Cmax, AUCinf, AUClast, AUCtau,T1/2, Tmax, Racc, CL/F, and Vz/F	Approximately 8 months
Changes between pre- and post-treatment levels of pS6RP and 4EBP1 levels in bone marrow aspirates and 4EBP1 in peripheral blood	Cycle 2 = 28 days; LGH447-mediated target modulation of the PIM pathway will be assessed from the collection of bone marrow biopsy and/or aspirates by flow cytometry, immunohistochemistry, or other methods as deemed appropriate. Decreases in the phosphorylation of markers (eg. S6RP and 4EBP1) will be measured in both pre- and post-dose bone marrow aspirate samples and peripheral blood samples.	baseline, Cycle 2 Day 1
Phase II: Absolute difference in ORR	Both observed and Bayesian estimates of absolute difference in ORR between the two arms will be calculated. The 80% confidence intervals and credible intervals for the difference will be provided. End of Study (defined as the time when all patients have completed at least 6 cycles of treatment or discontinued treatment, or have been lost to follow up, whichever occurs first.	29 months (End of Study)
Disease Control Rate	Proportion of patients with a best overall response of sCR, CR, VGPR, PR, MR, or SD, using International Myeloma Working Group Criteria with modification. End of Study (defined as the time when all patients have completed at least 6 cycles of treatment or discontinued treatment, or have been lost to follow up, whichever occurs first.	29 months (End of Study)
Progression Free Survival	Defined as the time from start of treatment to the date of event defined as the first documented PD/relapse, or death due to any cause, whichever comes first. End of Study (defined as the time when all patients have completed at least 6 cycles of treatment or discontinued treatment, or have been lost to follow up, whichever occurs first.	29 months (End of Study)
Time to response	The time between date of randomization until first documented best overall response (sCR, CR, VPGR or PR). End of Study (defined as the time when all patients have completed at least 6 cycles of treatment or discontinued treatment, or have been lost to follow up, whichever occurs first.	29 months (End of Study)
Duration of Response	Defined as the duration from the first documented onset of PR or better response to the date of documented PD/relapse or death due to multiple myeloma. End of Study (defined as the time when all patients have completed at least 6 cycles of treatment or discontinued treatment, or have been lost to follow up, whichever occurs first.	29 months (End of Study)

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• Results for CLGH447X2103C can be found on the Novartis Clinical Trial Results Website

Study record dates

Study Major Dates

• Study Start (Actual): July 23, 2014
• Primary Completion (Actual): October 28, 2015
• Study Completion (Actual): October 28, 2015

Study Registration Dates

• First Submitted: May 1, 2014
• First Submitted That Met QC Criteria: May 19, 2014
• First Posted (Estimate): May 21, 2014

Study Record Updates

• Last Update Posted (Actual): December 17, 2020
• Last Update Submitted That Met QC Criteria: December 16, 2020
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Keywords: LGH447,; PI3K inhibitor; BYL719,; multiple myeloma,; relapsed and refractory,; pan-PIM inhibitor,; PIM Kinase,
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell
• Other Study ID Numbers: CLGH447X2103C; 2013-004959-21 (EudraCT Number)