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Dose escalation of CJM112 in combination with a fixed dose of PDR001

Dose escalation of LCL161 in combination with a fixed dose of PDR001

PDR001

CJM112

LCL161

Novartis Pharmaceuticals

The purpose of this study is to assess the safety, tolerability, and identify the recommended doses of single agent CJM112, and of CJM112 or LCL161 in combination with PDR001, in patients with relapsed and/or refractory multiple myeloma.

The study is comprised of 3 treatment arms:

* Single agent CJM112 (Arm A)
* A fixed dose of PDR001 in combination with CJM112 (Arm B)
* A fixed dose of PDR001 in combination with LCL161 (Arm C)

Patients may switch from treatment on Arm A to the corresponding CJM112 dose level on Arm B at the time of disease progression if that dose level has been declared safe, and if patients do not have any DLTs on single agent CJM112. Otherwise, patients will switch to a lower dose level that has been declared safe. No other cross-over between treatment arms is allowed.

Study of Single Agent CJM112, and PDR001 in Combination With LCL161 or CJM112 in Patients With Multiple Myeloma

Phase I/Ib, Multi-center, Open-label, Study of Single Agent CJM112, and PDR001 in Combination With LCL161 or CJM112 in Patients With Relapsed and/or Refractory Multiple Myeloma

number of patients reporting dose limiting toxicity

Number of patients with treatment-related adverse events as assessed by CTCAE v4.0

Frequency of patients requiring a dose interruption

Frequency of patients discontinuing treatment.

Frequency of patients requiring a dose reduction.

Presence and/or concentration of anti-PDR001, and anti-CJM112 antibodies

Dose-escalation, LGH447 in combinatinon with BYL719

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

LGH447 alone (dosing according to single-agent RDE)

LGH447

BYL719

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 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

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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

Vulnerability and therapeutic changes in older patients with multiple myeloma.

Komivi AGBETSIVI, DR

VIGNARD Patricia, Dr

Catherine Cattenoz, Dr

Jean -Richard EVEILLARD, Dr

François Puisieux, Pr

Jean -Yves NIEMIER, Dr

Frédérique Retornaz, Dr

Véronique Brunel, Dr

Laure De Decker, Dr

The aim of this study is to determine whether the presence of vulnerability detected by geriatricians is associated with treatment discontinuation in older patient. During the comprehensive geriatric assessment realized before the decision-treatment, the following data are recorded and their impact in the therapeutic changes will also be analysed: comorbidity, age, depression, functional status, the cognitive impairment and malnutrition.

Vulnerability and Therapeutic Changes in Older Patients With Multiple Myeloma.

The primary outcome is either :

* early interruption of treatment
* dose reduction \> 20% during treatment
* discontinuous treatment

These outcomes will be measured every 6 months during the 2 years of follow up

vulnerability related to toxicities, vulnerability related to multiple myeloma or geriatric vulnerability.

early interruption of treatment, dose reduction during treatment, discontinuous treatment

hematologic toxicity, neurotoxicity, gastrointestinal toxicity, deep vein thrombosis, pulmonary embolism, infections with antibiotic use

Nantes University Hospital

Hematologic Neoplasms

This is a multi-center, open-label, dose escalation, Phase 1 study of oral LGH447 in Japanese patients with relapsed and/or refractory multiple myeloma for which no standard effective treatment options exist.

The study consists of a dose escalation part to estimate the maximum tolerated dose and/or the recommended dose for expansion and a dose expansion part to further assess safety and preliminary anti-cancer activity of LGH447 at the maximum tolerated dose and/or the recommended dose for expansion.

Dose Escalation Study of LGH447 in Japanese Patients With Relapsed and/or Refractory Hematologic Malignancies

A Multi-center, Open-label, Dose Escalation, Phase 1 Study of Oral LGH447 in Japanese Patients With Relapsed and/or Refractory Hematologic Malignancies

Estimate the maximum tolerated dose and/or recommended dose for expansion of LGH447 in Japanese patients

Adverse events, serious adverse events, changes in laboratory values, and electrocardiograms

PK parameters such as AUC, Cmax, Tmax, T1/2. Cycle = 28 days

Describe any preliminary anti-cancer activity associated with LGH447 based on International Myeloma Working group Criteria with modification.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study of Single Agent CJM112, and PDR001 in Combination With LCL161 or CJM112 in Patients With Multiple Myeloma	NCT03111992	Multiple Myelom...	PDR001 CJM112 LCL161	18 Years -	Novartis
Study of the Safety and Effectiveness of LGH447 and BYL719 in Patients With Relapsed and Refractory Multiple Myeloma	NCT02144038	Relapsed and Re...	LGH447 BYL719	18 Years -	Novartis
Vulnerability and Therapeutic Changes in Older Patients With Multiple Myeloma.	NCT02063113	Multiple Myelom...	Vulnerability a...	70 Years - 100 Years	Nantes University Hospital
Study of Single Agent CJM112, and PDR001 in Combination With LCL161 or CJM112 in Patients With Multiple Myeloma	NCT03111992	Multiple Myelom...	PDR001 CJM112 LCL161	18 Years -	Novartis
Dose Escalation Study of LGH447 in Japanese Patients With Relapsed and/or Refractory Hematologic Malignancies	NCT02160951	Multiple Myelom...	LGH447	18 Years -	Novartis
Vulnerability and Therapeutic Changes in Older Patients With Multiple Myeloma.	NCT02063113	Multiple Myelom...	Vulnerability a...	70 Years - 100 Years	Nantes University Hospital
Study of the Safety and Effectiveness of LGH447 and BYL719 in Patients With Relapsed and Refractory Multiple Myeloma	NCT02144038	Relapsed and Re...	LGH447 BYL719	18 Years -	Novartis

Spots Global Cancer Trial Database for multiple myeloma,