Carfilzomib Thalidomide and Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma
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|ClinicalTrials.gov Identifier: NCT03140943|
Recruitment Status : Recruiting
First Posted : May 4, 2017
Last Update Posted : November 6, 2017
All patients with multiple myeloma (MM) are destined to relapse even with the best available approved agents. Median OS from diagnosis in the current era is reported at 5.4 years. Given that myeloma remains an incurable disease, future improved OS is therefore reliant on the expansion of salvage options for patients with RRMM.
Carfilzomib (formerly PR-171) is a tetrapeptide epoxyketone-based irreversible inhibitor of the 20S proteasome. This second-generation proteasome inhibitor (PI) is structurally and mechanistically different to the dipeptide boronic acid PI, bortezomib. Compared to bortezomib, carfilzomib showed less off-target activity that may account for the reduced myelosuppression and reduced neuropathy that is observed compared to bortezomib. As monotherapy, carfilzomib has demonstrated robust and durable activity in heavily pre-treated patients with RRMM in phase I and II trials The idea of combining a PI and an immunomodulatory drug (IMiD) such as thalidomide or lenalidomide is attractive in MM due to the efficacy previously demonstrated with combination bortezomib, thalidomide and dexamethasone. Such efficacy obviates the need for chemotherapy that is known to induce genetic instability and in turn gives rise to secondary cancers. In combination with lenalidomide (25mg), Niesvizky and colleagues have demonstrated a maximum planned dose (MPD) of carfilzomib as 20/27 mg/m2 with promising safety and efficacy. Combination carfilzomib and thalidomide, as opposed to lenalidomide, is practically a more affordable regimen that will be more applicable to the Asia-Pacific region.
|Condition or disease||Intervention/treatment||Phase|
|Relapsed and/or Refractory Multiple Myeloma||Drug: Carfilzomib, Thalidomide and Dexamethasone||Phase 2|
All patients will continue treatment for 18 cycles (12 induction cycles, 6 maintenance cycles) unless development of adverse events that require early cessation of treatment. Patients will be followed up for progression and survival until 1 year following the completion of the last patient's final cycle of induction therapy.
Proteasome inhibitors and IMiDs have different but overlapping mechanisms of anti-MM activity. In the clinical setting, both proteasome inhibitors and IMiDs enhance the activity of dexamethasone, and synergy has previously been demonstrated between the first in class proteasome inhibitor, bortezomib and the immunomodulatory drug lenalidomide. Relative to bortezomib, carfilzomib demonstrated increased apoptosis in MM cell lines, and induce high ORR in both bortezomib-naïve and resistant patients.
We hypothesise that carfilzomib will induce a synergistic anti-myeloma activity when combined with the first in class immunomodulatory drug thalidomide, and dexamethasone. Thalidomide is a cheaper immunomodulatory drug that is more accessible in the Asia-Pacific region compared to lenalidomide. This makes the combination of carfilzomib, thalidomide and dexamethasone a more viable salvage option for patients in this region.
In the PX-171-006 study, combination carfilzomib lenalidomide and dexamethasone induced a CR/VGPR in 59% of patients. The maximum per protocol doses of carfilzomib (27g/m2) was used safely with full dose lenalidomide (25mg po daily days 1-21 every 28 days) and dexamethasone (40 mg po weekly), and the MTD of carfilzomib was not reached.
Carfilzomib 56mg/m2 was tolerable in phase II trials and induced durable responses in patients with relapsed and/or refractory myeloma. The most common grade 3/4 side effects of lymphopenia (43%), thrombocytopenia (32%), hypertension (25%), and pneumonia (18%) are not expected to overlap significantly with the expected side effects of thalidomide .
We will combine carfilzomib 20/56mg per m2 in combination with thalidomide 100mg daily and dexamethasone 40mg weekly. The rationale for dose escalation of carfilzomib to 56mg/m2 is based on two findings: a) the 20/56mg/m2 dose escalation was well tolerated in the PX-171-007 trial and b) no dose limiting toxicities were seen with carfilzomib 20/27mg/m2 when combined with lenalidomide and dexamethasone in patients with RRMM who were heavily pre-treated, in the PX-171-006 and PX-171-009 trial. The rationale for assigning an equal number of patients between the ALLG sites and AMN sites is to avoid bias with respect to potential biological differences between patients in Asia and Australia/New Zealand.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||100 participants|
|Intervention Model:||Single Group Assignment|
|Intervention Model Description:||All patients will continue treatment for 18 cycles (12 induction cycles, 6 maintenance cycles) unless development of adverse events that require early cessation of treatment. Patients will be followed up for progression and survival until 1 year following the completion of the last patient's final cycle of induction therapy.|
|Masking:||None (Open Label)|
|Official Title:||Single Arm, Multicentre Study of Carfilzomib in Combination With Thalidomide and Dexamethasone (CaTD) in Patients With Relapsed and/or Refractory Multiple Myeloma (RRMM)|
|Actual Study Start Date :||September 13, 2017|
|Estimated Primary Completion Date :||June 1, 2019|
|Estimated Study Completion Date :||June 1, 2022|
|Experimental: Carfilzomib, Thalidomide and Dexamethasone||
Drug: Carfilzomib, Thalidomide and Dexamethasone
Carfilzomib will be given on days 1,2,8,9,15,16 in a 4-week (28 day) cycle during induction cycles 1-12, followed by days 1,2,15,16 in a 4-week cycle during maintenance cycles 13-18 (section 4.0) Dexamethasone, 40mg po will be given on days 1,8,15, 22 in a 4-week cycle during induction cycles 1-12, followed by days 1,15, in a 4-week cycle during maintenance cycles 13-18.
Thalidomide, 100mg po will be given daily during induction cycles 1-12 only.
- Progression free survival (PFS) [ Time Frame: 5 years or until disease progression ]To assess the progression free survival (PFS) in patients with RRMM who have had 1 to 3 prior lines of therapies, treated with combination carfilzomib, thalidomide and dexamethasone (CaTD)
- Overall survival (OS) [ Time Frame: 5 years ]Defined as the duration from the start of treatment (C1D1) to death from any cause.
- Overall Rate of Response (ORR) [ Time Frame: anytime from commencement of treatment to the end of study baseline until disease progression, unmanageable adverse event or death, whichever occurs first, approximately up to 3 years ]percentage of patients enrolled that achieve a complete response (CR), or stringent complete response (sCR), or very good partial response (VGPR), or partial response (PR) based on the International Myeloma Working Group criteria
- Duration of response (DOR) [ Time Frame: 5 years ]Defined as the duration from the first response to the time of progression. Duration of response will be censored by deaths due to causes other than progression
- Time to progression (TTP) [ Time Frame: 5 years ]Defined as the duration from the start of treatment (C1D1) to disease progression or relapse based upon IMWG criteria, with deaths due to causes other than progression censored
- Number of Participants affected by Adverse Events [ Time Frame: Baseline up to 4 Weeks after the last dose of study drug administration ]An AE is any untoward medical occurrence attributed to study drug in a participant who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
- Quality of life of participants on treatment [ Time Frame: Approximately 3 years ]Health-related quality of life (HR-QOL) will be measured by the European standardized instrument EuroQoL EQ-5D-5L
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03140943
|Contact: Wee Joo Chng||6779 email@example.com|
|Contact: Adeline Linfirstname.lastname@example.org|
|Queen Mary Hospital||Not yet recruiting|
|Hong Kong, Hong Kong|
|Korea, Republic of|
|Not yet recruiting|
|South Korea, Korea, Republic of|
|National University Hospital||Recruiting|
|National Taiwan University||Not yet recruiting|
|Principal Investigator:||Wee Joo Chng||National University Hospital, Singapore|