A Phase 2 clinical trial of orally taken investigational product (called MLN9708) in adult patients with returning and/or not responding Follicular Lymphoma

• Register: EUCTR
• Last refreshed on: 3 July 2017
• Main ID: EUCTR2013-002302-32-BE
• Date of registration: 21/08/2013
• Prospective Registration: Yes
• Primary sponsor: Millennium Pharmaceuticals, Inc.
• Public title: A Phase 2 clinical trial of orally taken investigational product (called MLN9708) in adult patients with returning and/or not responding Follicular Lymphoma
• Scientific title: An Open-label, Multicenter, Phase 2 Study of Oral MLN9708 in Adult Patients With Relapsed and/or Refractory Follicular Lymphoma
• Date of first enrolment: 12/11/2013
• Target sample size: 58
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2013-002302-32
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: yes Other trial design description: Part1:lead-in dose-finding phase; Part 2:phase 2, tandem 2-step biomarker evaluation trial design If controlled, specify comparator, Other Medicinial Product: Placebo: Other: Number of treatment arms in the trial: 1
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Belgium, Canada, Italy, Spain, United Kingdom, United States

Contacts

• Name: Drug Information Call Centre
• Affiliation: Millennium Pharmaceuticals, Inc.

• Name: Drug Information Call Centre
• Affiliation: Millennium Pharmaceuticals, Inc.

Key inclusion & exclusion criteria

Inclusion criteria:
Each patient must meet all of the following inclusion criteria to be enrolled in the study:
1. Male or female patients 18 years or older.
2. Patients must have a pathologically confirmed diagnosis of NHL (for the lead-in dose finding phase) and FL (for phase 2).
3. Patients must have radiographically or clinically measurable disease. Measurable disease is defined as at least 1 measurable tumor mass (> 1.5 cm in the long axis and > 1.0 cm in the short axis) that has not been previously irradiated, or has grown since
previous irradiation.
4. Patients must be relapsed and/or refractory after at least 1 prior therapy (excluding radiation) with documented progressive disease at the time of enrollment.
5. Patients must have Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
6. Female patients who:
• Are 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 the time of signing the informed consent 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 patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.).
7. Male patients, even if surgically sterilized (ie, status postvasectomy), who:
• 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 patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods for the female partner] and withdrawal are not acceptable methods of contraception.).
8. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
9. Suitable venous access for the study-required blood sampling for PK sampling for the lead-in dose-finding phase.
10. Clinical laboratory values as specified below within 3 days before the first dose of study drug:
Absolute neutrophil count (ANC) = 1,000/mm3 and platelet count = 75,000/mm3 (or = 50,000/mm3 if there is known malignant bone marrow infiltration due to the underlying disease).
• Total bilirubin must be < 1.5 x the upper limit of normal (ULN).
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) must be < 2.5 x the ULN. AST and ALT may be elevated up to 5 x the ULN if the elevation can be reasonably ascribed to the presence of disease in liver.
• Serum creatinine must be < 2.0 mg/dL and/or creatinine clearance or calculated creatinine clearance > 40 mL/min.
11. Recovered (ie, = Grade 1 toxicity or baseline levels) from toxicities of prior anticancer therapy.
12. If the trial proceeds to the second step on the basis of the tandem 2-step design, patients must be confirmed PSMB1 positive at the central laboratory before treatment.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 40
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 18
Exclusion criteria:
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1. Peripheral neuropathy = Grade 2 on clinical examination, or Grade 1 with pain.
2. Female patients who are lactating and breastfeeding or have a positive serum pregnancy test during the Screening period.
3. Autologous stem cell transplant within 6 months before Day 1 of Cycle 1, or prior allogeneic stem cell transplant at any time.
4. Major surgery within 14 days before the first dose of study drug.
5. Infection requiring systemic antibiotic therapy or other serious infection within 14 days before the first dose of study drug.
6. Comorbid systemic illnesses or other severe concurrent disease that, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
7. Evidence of current uncontrolled cardiovascular conditions including uncontrolled hypertension, severe uncontrolled ventricular arrhythmias, unstable angina, New York Heart Association (NYHA) Class III or IV cardiac disease, or myocardial infarction within the past 6 months.
8. Diarrhea > Grade 1 on the basis of the NCI CTCAE categorization.
9. Systemic antineoplastic (including glucocorticoids > the equivalent of 15 mg of prednisone daily), experimental, or radiation therapy within 21 days before the first dose of study drug.
10. Prior treatment with rituximab or other unconjugated antibody treatment within 42 days (21 days if clear evidence of PD or immediate treatment is mandated).
11. Treatment with radioimmunoconjugates or toxin immunoconjugates within 12 weeks before the first dosing of study treatment.
12. Systemic treatment 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) within 14 days before the first dose of MLN9708.
13. Ongoing systemic therapy with corticosteroids (up to 15-mg prednisone or equivalent per day is allowed, as are topical products and eye drops containing corticosteroids)
14. Central nervous system (CNS) involvement that is clinically uncontrolled or newly diagnosed in the last 4 months. Patients who have a history of CNS involvement, but no evidence of active CNS disease are not excluded.
15. Ongoing or active systemic viral infection, known human immunodeficiency virus (HIV) positive, known active hepatitis B virus or known active hepatitis C virus.
16. 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 nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection. Transformed FL patients are also excluded from the phase 2 portion.
17. Platelet transfusions within 3 days before the 1st dose of study drug.
18. Inability to swallow capsules, or inability or unwillingness to avoid taking anything by mouth except for water and prescribed medication for 2 hours before and 1 hour after dose of MLN9708.
19. Known allergy to boron or excipients in the formulation.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Follicular Lymphoma
MedDRA version: 18.1 Level: LLT Classification code 10029478 Term: Nodular lymphoma System Organ Class: 100000004864

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Product Name: Ixazomib Capsules, 4.0mg
Product Code: MLN9708
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: ixazomib citrate
CAS Number: 1239908-20-3
Current Sponsor code: MLN9708
Other descriptive name: MLN9708
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 4.0-

Product Name: Ixazomib Capsules, 3.0mg
Product Code: MLN9708
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: ixazomib citrate
CAS Number: 1239908-20-3
Current Sponsor code: MLN9708
Other descriptive name: MLN9708
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 3.0-

Product Name: Ixazomib Capsules, 2.3mg
Product Code: MLN9708
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: ixazomib citrate
CAS Number: 1239908-20-3
Current Sponsor code: MLN9708
Other descriptive name: MLN9708
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 2.3-

Primary Outcome(s)

Secondary Objective: • To determine the recommended phase 2 dose (RP2D) to be used to treat patients with FL on the basis of evaluation of weekly oral ixazomib dosing during the lead-in dose-finding phase in patients with any type of NHL (all comers)
• To evaluate additional measures of anti-tumor activity of ixazomib in patients with FL including PFS, rate of disease control, time to response (TTR), and duration of response (DOR)
• To evaluate a PSMB1 polymorphic marker as a candidate selection biomarker for ixazomib in patients with FL
• To evaluate safety and tolerability of ixazomib at the RP2D
• To characterize the PK of oral ixazomib in patients with NHL

Main Objective: The primary objective is to evaluate the anti-tumor activity of oral ixazomib as measured by ORR in adult patients with relapsed and/or refractory FL.

Primary end point(s): The primary endpoint is overall response (CR + PR) rate (ORR).

Timepoint(s) of evaluation of this end point: during phase 2 portion of the study

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: • PFS is defined as the time from the date of first dose of study drug to the date of first documented PD or death.
• Rate of disease control is evaluated through the study
• TTR is defined as the time from the date of first dose of study drug to the date of the first documentation of a confirmed response in a patient who responded.
• DOR is defined as the time from the date of first documentation of a confirmed response to the date of first documented PD.

Secondary end point(s): The secondary endpoints include:
• RP2D
• PFS
• Rate of disease control (defined as the sum of CR, PR, and stable disease [SD] for = 6 months)
• TTR
• DOR
• Response rates in FL patients positive versus negative for the PSMB1 polymorphic marker
• Safety and tolerability of MLN9708 treatment based on AEs, serious adverse events (SAEs), assessments of clinical laboratory values, vital sign measurements, and physical examination
• Assessment of single- and multiple-dose plasma PK parameters including, but not limited to the single-dose maximum (peak) concentration (Cmax), Tmax, and the area under the plasma concentration versus time curve (AUC) from zero to the time of the last quantifiable plasma concentration (AUClast)

Secondary ID(s)

C16017

Source(s) of Monetary Support

Millennium Pharmaceuticals, Inc.