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

NCT02144038 | Completed Phase 1

• 2 other identifiers: CLGH447X2103C2013-004959-21
• Study Type: interventional
• Target: 20
• Locations: 5 countries
• Sites: 8

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.

Conditions

Relapsed and Refractory Multiple Myeloma

Keywords

multiple myeloma,; relapsed and refractory,; LGH447,; pan-PIM inhibitor,; PIM Kinase,; BYL719,; PI3K inhibitor

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (9)

• Phase II: Percent change of ORR (Overall Response Rate) between the two arms

  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.

  23 months

• Determine single and multiple dose Pharmacokinetics (PK) profiles

  Approximately 8 months

• Changes between pre- and post-treatment levels of pS6RP and 4EBP1 levels in bone marrow aspirates and 4EBP1 in peripheral blood

  baseline, Cycle 2 Day 1

• Phase II: Absolute difference in ORR

  29 months (End of Study)

Study Arms (3)

Phase Ib: LGH447 + BYL719

EXPERIMENTAL

Dose-escalation, LGH447 in combinatinon with BYL719

Drug: LGH447; Drug: BYL719

Phase II: LGH447 + BYL719

EXPERIMENTAL

LGH447 + BYL719 (dosing according to MTD/RP2D from Phase Ib portion of the study)

Drug: LGH447; Drug: BYL719

Phase II: LGH447 alone

EXPERIMENTAL

LGH447 alone (dosing according to single-agent RDE)

Drug: LGH447

Interventions

LGH447 DRUG

pan-PIM inhibitor

Phase II: LGH447 + BYL719; Phase II: LGH447 alone; Phase Ib: LGH447 + BYL719

BYL719 DRUG

PI3K-alpha inhibitor

Phase II: LGH447 + BYL719; Phase Ib: LGH447 + BYL719

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (8)

University of Texas/MD Anderson Cancer Center Dept.ofMDAndersonCancerCtr(SC)

Houston, Texas, 77030-4009, United States

Location

Seattle Cancer Care Alliance Oncology Dept

Seattle, Washington, 98105, United States

Location

University of Wisconsin / Paul P. Carbone Comp Cancer Center Dept of Onc.

Madison, Wisconsin, 53792-6164, United States

Location

Novartis Investigative Site

Prahran, Victoria, 3181, Australia

Location

Novartis Investigative Site

Heidelberg, 69120, Germany

Location

Novartis Investigative Site

Kiel, 24105, Germany

Location

Novartis Investigative Site

Milan, MI, 20133, Italy

Location

Novartis Investigative Site

Singapore, 169608, Singapore

Location

Related Links

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

MeSH Terms

Conditions

Recurrence; Multiple Myeloma

Interventions

LGH-447; Alpelisib

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 1, 2014
• First Posted: May 21, 2014
• Study Start: July 23, 2014
• Primary Completion: October 28, 2015
• Study Completion: October 28, 2015
• Last Updated: December 17, 2020

Record last verified: 2018-04

Locations

SG (1); US (3); AU (1); DE (2); IT (1)