Relapsed and Refractory Multiple MyelomaPhase 1NCT02144038
Study of the Safety and Effectiveness of LGH447 and BYL719 in Patients With Relapsed and Refractory Multiple Myeloma
A Phase 1 study testing LGH447 and BYL719 in people with Relapsed and Refractory Multiple Myeloma, run by Novartis Pharmaceuticals at 8 sites in 5 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Relapsed and Refractory Multiple Myeloma
- What is being tested?
- LGH447 and BYL719
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 20 participants
- Where
- 8 sitesin 5 countries
- Study dates
- 23 Jul 2014to 28 Oct 2015
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 15Show fewer
- 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
Trial locations and contacts
8 sites in 5 countries.
8 sites in 5 countries
United States3 sites
University of Texas/MD Anderson Cancer Center Dept.ofMDAndersonCancerCtr(SC)
Houston, Texas, 77030-4009
University of Wisconsin / Paul P. Carbone Comp Cancer Center Dept of Onc.
Madison, Wisconsin, 53792-6164
Seattle Cancer Care Alliance Oncology Dept
Seattle, Washington, 98105
Germany2 sites
Novartis Investigative Site
Heidelberg, 69120
Novartis Investigative Site
Kiel, 24105
About this study
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
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
- Being tested
- LGH447, BYL719
- Keywords
- multiple myeloma,, relapsed and refractory,, LGH447,, pan-PIM inhibitor,, PIM Kinase,, BYL719,, PI3K inhibitor
- Medical subject headings
- Recurrence, Multiple Myeloma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LGH447Drug
pan-PIM inhibitor
BYL719Drug
PI3K-alpha inhibitor
| Study group | Role | What they receive |
|---|---|---|
| Phase Ib: LGH447 + BYL719 | Experimental | Dose-escalation, LGH447 in combinatinon with BYL719 Receives: Drug: LGH447; Drug: BYL719 |
| Phase II: LGH447 + BYL719 | Experimental | LGH447 + BYL719 (dosing according to MTD/RP2D from Phase Ib portion of the study) Receives: Drug: LGH447; Drug: BYL719 |
| Phase II: LGH447 alone | Experimental | LGH447 alone (dosing according to single-agent RDE) Receives: Drug: LGH447 |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 29 months (End of Study)
Secondary outcomes (9)
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.
Measured: 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.
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 29 months (End of Study)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 May 2014 (estimated)
- Study start23 Jul 2014
- Primary completion28 Oct 2015
- Study completion28 Oct 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Relapsed and Refractory Multiple MyelomaStudies of the same condition, open and under way.
- More trials run by Novartis PharmaceuticalsThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 20 participants (actual)
Sponsor and investigators
- Lead sponsor
- Novartis Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02144038
- Sponsor's protocol ID
- CLGH447X2103C
- Other IDs
- 2013-004959-21
- Status last verified
- Apr 2018
- First submitted
- 1 May 2014
- Last updated
- 17 Dec 2020
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 17 Dec 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT02144038
- Acronym / sponsor ID
- CLGH447X2103C
- Conditions
- Relapsed and Refractory Multiple Myeloma
- Keywords
- multiple myeloma,, relapsed and refractory,, LGH447,, pan-PIM inhibitor,, PIM Kinase,, BYL719,, PI3K inhibitor
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 20 participants (actual)
- Lead sponsor
- Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
- Study start
- 23 Jul 2014 (actual)
- Primary completion
- 28 Oct 2015 (actual)
- Study completion
- 28 Oct 2015 (actual)
- First posted
- 21 May 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Phase Ib: LGH447 + BYL719 | Experimental | Drug: LGH447, Drug: BYL719Dose-escalation, LGH447 in combinatinon with BYL719 |
| Phase II: LGH447 + BYL719 | Experimental | Drug: LGH447, Drug: BYL719LGH447 + BYL719 (dosing according to MTD/RP2D from Phase Ib portion of the study) |
| Phase II: LGH447 alone | Experimental | Drug: LGH447LGH447 alone (dosing according to single-agent RDE) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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:
- 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
Key exclusion criteria (15 listed)
- 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:
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| LGH447pan-PIM inhibitor | Drug | Phase II: LGH447 + BYL719, Phase II: LGH447 alone, Phase Ib: LGH447 + BYL719 |
| BYL719PI3K-alpha inhibitor | Drug | Phase II: LGH447 + BYL719, Phase Ib: LGH447 + BYL719 |
Primary outcome
Phase Ib: Number of Total Dose-limiting Toxicities (DLT)
Time frame: Cycle 1 (28 days)
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.
Phase II: Overall Response Rate (ORR) as assessed by Investigators
Time frame: 29 months (End of Study)
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.
9 secondary outcomes
Phase II: Percent change of ORR (Overall Response Rate) between the two arms
Time frame: 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.
Time frame: 23 months
Determine single and multiple dose Pharmacokinetics (PK) profiles
Time frame: Approximately 8 months
Changes between pre- and post-treatment levels of pS6RP and 4EBP1 levels in bone marrow aspirates and 4EBP1 in peripheral blood
Time frame: baseline, Cycle 2 Day 1
Phase II: Absolute difference in ORR
Time frame: 29 months (End of Study)
Disease Control Rate
Time frame: 29 months (End of Study)
Progression Free Survival
Time frame: 29 months (End of Study)
Time to response
Time frame: 29 months (End of Study)
Duration of Response
Time frame: 29 months (End of Study)
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Dec 2020.
- Results for CLGH447X2103C can be found on the Novartis Clinical Trial Results WebsiteLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Novartis Pharmaceuticals study director
Novartis Pharmaceuticals
8 sites in 5 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing LGH447 and BYL719 in people with Relapsed and Refractory Multiple Myeloma, run by Novartis Pharmaceuticals at 8 sites in 5 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 17 Dec 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 8 sites in United States, Germany, Australia, Italy, Singapore. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Phase Ib: Number of Total Dose-limiting Toxicities (DLT) (time frame: Cycle 1 (28 days)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Dec 2020.