Ixazomib in Combination With Thalidomide - Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma

Sponsor

Arbeitsgemeinschaft medikamentoese Tumortherapie (Other)

Overall Status

Completed

CT.gov ID

NCT02410694

Collaborator

(none)

Enrollment

Locations

Arm

Actual Duration (Months)

5.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Overview of Study Design:

This is an open phase II, single-arm, multi-center study to evaluate progression free survival in patients receiving ixazomib in combination with thalidomide and dexamethasone (ITD) followed by an ixazomib maintenance phase of a maximum period of 12 months.

The patient population will consist of adult male and female patients with multiple myeloma (MM) with relapsed and/or refractory disease after at least one prior treatment line.

In case of enrollment patients will receive ixazomib 4.0mg at days 1, 8, 15, thalidomide 100mg at days 1 to 28 (50mg in patients aged ≥75 years), and dexamethasone 40mg (20mg in patients aged ≥75 years) at days 1, 8, 15 of a 28-day treatment cycle. The proposed number of cycles is 8. Treatment will be discontinued in case of progressive disease or in case of no response after 4 cycles (≤ SD after 4 cycles). After discontinuation of therapy an end of treatment visit (EOT) will be performed within 14 days after the last dose of the last combination treatment cycle.

After 8 cycles of ITD therapy, maintenance treatment with 4.0mg ixazomib (3.0mg in patients aged ≥ 75 years at first day of maintenance phase) on days 1, 8, 15 of 28-day cycles will be administered to patients with ≥ MR for a maximum period of 12 months. Patients who completed less than 8 cycles of ITD treatment do not qualify for maintenance phase.

Follow-up visits will be performed in 3-monthly intervals until the last patient on ixazomib maintenance therapy has concluded or discontinued the maintenance phase.

A safety analysis will be conducted after enrollment of the first 6 patients and completion of at least two cycles in every patient.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: Ixazomib Drug: Thalidomide Drug: Dexamethasone	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

90 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Ixazomib in Combination With Thalidomide - Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma

Actual Study Start Date :

Apr 1, 2015

Actual Primary Completion Date :

Mar 28, 2019

Actual Study Completion Date :

May 2, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ixazomib-Thalidomide-Dexamethasone Combination therapy of: Ixazomib 4.0mg at days 1, 8, 15, Thalidomide 100mg at days 1 to 28 (50mg in patients aged ≥75 years), Dexamethasone 40mg (20mg in patients aged ≥75 years) at days 1, 8, 15 of a 28-day treatment cycle. After 8 cycles of ITD therapy, maintenance treatment with 4.0mg ixazomib (3.0mg in patients aged ≥ 75 years at first day of maintenance phase) on days 1, 8, 15 of 28-day cycles will be administered to patients with ≥ MR for a maximum period of 12 months.	Drug: Ixazomib Drug: Thalidomide Drug: Dexamethasone

Arm

Intervention/Treatment

Experimental: Ixazomib-Thalidomide-Dexamethasone

Combination therapy of: Ixazomib 4.0mg at days 1, 8, 15, Thalidomide 100mg at days 1 to 28 (50mg in patients aged ≥75 years), Dexamethasone 40mg (20mg in patients aged ≥75 years) at days 1, 8, 15 of a 28-day treatment cycle. After 8 cycles of ITD therapy, maintenance treatment with 4.0mg ixazomib (3.0mg in patients aged ≥ 75 years at first day of maintenance phase) on days 1, 8, 15 of 28-day cycles will be administered to patients with ≥ MR for a maximum period of 12 months.

Drug: Ixazomib

Drug: Thalidomide

Drug: Dexamethasone

Outcome Measures

Primary Outcome Measures

Progression free survival (PFS) [start of combination therapy to progressive disease or death due to any cause whichever occurs first, up to 4.5 years]

Secondary Outcome Measures

Overall Response Rate (ORR) [best and first response since start of therapy, up to 4,5 years]
Overall Survival (OS) [start of therapy to death, up to 4,5 years]
Renal Response in a subgroup of patients with baseline GFR 15-30ml/min [start of therapy to best renal response, up to 4,5 years]
Determination of safety by reporting of adverse events [start of therapy to end of study therapy (appr. 2 yrs)]
Reporting of adverse event as a measure of safety and tolerability
Assessment of prognostic values of risk factors at diagnosis incl. clinical assessment and cytogenetic abnormalities [screening to end of study (appr. 2 yrs)]
Correlation between altered expressions of specifically selected genes and patient´s response to the treatment regimen [screening to end of study (appr. 2 yrs)]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Male or female patients 18 yrs or older.
Voluntary written consent
Patients in need of therapy with a diagnosis of relapsed or refractory multiple myeloma who had at least one prior treatment line
Patients must have measurable disease defined by at least 1 of the following criteria:

Serum M-protein ≥ 10g/l
Urine M-protein ≥ 200mg/24h
Serum free light chain assay: involved serum light chain ≥ 10mg/dl provided that free light chain ration is abnormal

Life expectancy > 3 months
ECOG (Eastern Cooperative Oncology Group) ≤ 2
• ANC ≥ 1.000/mm3 and platelet count ≥ 50.000/mm3

Total bilirubin ≤ 2 x ULN
ALT and AST ≤ 3 x ULN
GFR ≥ 15ml/min as calculated by cockroft-Gault equation

Female patients who:

Are older than 50 years and postmenopausal for at least 1 year before the screening visit, OR
Are surgically sterile, OR
If they are of childbearing potential, agree to practice 2 effective methods of contraception at the same time, from 4 weeks before starting study therapy through 90 days after the last dose of study drug, OR
Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.)
Are informed and understand the possible consequences of the teratogenic potential of thalidomide
Male patients, even if surgically sterilized (i.e., status post-vasectomy), must agree to one of the following:
Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR
Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.)
Are informed and understand the possible consequences of the teratogenic potential of thalidomide

Disease free of prior malignancies for ≥ 2 years with exception of curatively treated basal cell, squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast if they have undergone complete resection.

Exclusion Criteria:

lactating females or have a positive serum pregnancy test
Failure to have fully recovered (i.e., ≤ Grade 1 toxicity) from the reversible effects of prior chemotherapy
Previous treatment with ixazomib
Previous treatment with bortezomib or thalidomide within the last 3 months prior to baseline visit
Primary refractory to, or relapsing during, or within ≤ 6 weeks after end of treatment with a proteasome inhibitor and/or thalidomide
Previous anti-cancer treatment within the last 21 days prior to baseline visit (cycle 1 / day 1), except corticosteroid therapy (40 - 160mg dexamethasone or corticosteroid dose equivalent per month)
Major surgery within 14 days before enrollment
Radiotherapy within 14 days before enrollment. If the involved field is small, 7 days will be considered a sufficient interval between treatment and administration of the ixazomib.
Central nervous system involvement
Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study enrollment
Evidence of current uncontrolled cardiovascular conditions
Systemic treatment, within 14 days before the first dose of ixazomib, with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort
Ongoing or active systemic infection, active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) positive
Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol
Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent
Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib including difficulty swallowing
Diagnosed or treated for another malignancy within 2 years before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with basal cell, squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast with are not excluded if they have undergone complete resection
Patient has ≥ Grade 3 peripheral neuropathy or Grade 2 with pain on clinical examination during the screening period
Participation in other interventional clinical trials, including those with other investigational agents not included in this trial, within 30 days of the start of this trial and throughout the duration of this trial

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ordensklinikum, KH der Barmherzigen Schwestern Linz, Interne I: Internistische Onkologie, Hämatologie und Gastroenterologie	Linz	Oberösterreich	Austria	4010
2	KH der Elisabethinen Linz, 1. Interne Abteilung	Linz	Oberösterreich	Austria	4020
3	Klinikum Wels-Grieskirchen, IV. Interne Abteilung	Wels	Oberösterreich	Austria	4600
4	Medizinische Universitätsklinik Graz, Klinische Abteilung für Hämatologie	Graz	Steiermark	Austria	8036
5	UK Innsbruck, Universitätsklinik für Innere Medizin, Klinische Abteilung für Hämatologie und Onkologie	Innsbruck	Tirol	Austria	6020
6	A.ö. BK Kufstein, Abteilung für Innere Medizin	Kufstein	Tirol	Austria	6330
7	LKH Feldkirch, Interne E	Feldkirch	Vorarlberg	Austria	6830
8	Kepler Universitätsklinikum Linz, Innere Medizin 3, Zentrum für Hämatologie und medizinische Onkologie	Linz		Austria	4021
9	Universitätsklinik der PMU Universitätsklinik für Innere Medizin III	Salzburg		Austria	5020
10	Wilhelminenspital	Vienna		Austria	A-1160
11	KH der Barmherzigen Brüder Wien, Innere Medizin	Wien		Austria	1020
12	Med. Universität Wien, Universitätsklinik f. Innere Medizin I, Klin. Abt. f. Hämatologie u. Hämostaseologie	Wien		Austria	1090
13	Faculty Hospital Brno and Faculty of Medicine MU Brno 2nd Internal Clinic	Brno		Czechia	639 00
14	Fakultní nemocnice Ostrava	Ostrava-Poruba		Czechia	708 52
15	Universitätsklinikum Leipzig - AöR Selbstständige Abteilung für Hämatologie, Internistische Onkologie und Hämostaseologie	Leipzig		Germany	04103
16	Universitätsklinikum Tübingen, Innere Medizin II	Tubingen		Germany	72076
17	Universitätsklinikum Würzburg, Medizinische Klinik und Poliklinik II Zentrum Innere Medizin	Wurzburg		Germany	97080