| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase I: To determine the dose of lenalidomide to be used in phase II part of the study.
Phase II: To investigate the effect of an anti-inflammatory therapy consisting of lenalidomide in combination with pioglitazone, dexamethasone and metronomic low-dose chemotherapy with treosulfan on the response rate in patients with relapsed or refractory or progressive multiple myeloma in third-line |
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| E.2.2 | Secondary objectives of the trial |
-To evaluate time to progression
-To evaluate time to partial response
-To evaluate overall survival.
-To evaluate quality of life.
-To evaluate tolerability and safety |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
-At least 18 years of age
-Must be able to adhere to the study visit schedule and other protocol requirements
-Must be diagnosed with multiple myeloma that is progressing or has relapsed with progressive disease after at least two different anti-myeloma treatments (including lenalidomide in one schedule phase II part only)
-In case of patients that have progressive disease after complete remission during preceding treatment: Serum monoclonal paraprotein (M-protein) level ≥0.5 g/dL for IgG, IgA myeloma and ≥0.05 g/dL for IgD myeloma or urine M-protein level ≥ 0.2 g excreted in a 24-hour collection sample
or
In case of progressive disease without complete remission during preceding treatment: > 25% increase of serum monoclonal paraprotein or urine M-protein in comparison to the preceding monoclonal paraprotein (M-protein) nadir in serum /urine M-protein nadir in a 24 hour collection sample
-Subjects must have been previously treated with lenalidomide for the phase II part. Any first- and second-line treatment is allowed for the phase I part. Phase I study inclusion is independent of pre-treatment in 1st line
-Sufficient bone marrow function: neutrophils ≥ 1x10E9/l, hemoglobin ≥10 g/dl, and platelets ≥ 100x10E9/l
-ECOG performance status score of 0, 1, or 2
-Subjects must discontinue all anti-myeloma drug or non-drug therapy prior to the first dose of study drug (at least 4 weeks)
-Required laboratory results: a) Liver function: Total bilirubin < 1.5 times of upper limit of local institution (ULN), SGPT, SGOT ≤ 2.5 times of upper limit of local institution . b) Renal function: serum creatinine ≤ 1.5 ULN c)PT-INR/PT <1.5 ULN
-Normal cardiac function
-Patients with prior thrombembolic event with adequate anticoagulation
-Life expectancy at least 3 months
-Written informed consent of the patient prior to screening procedures
•Female subjects of childbearing potential must:
•Understand that the study medication has a teratogenic risk
•Be capable of complying with effective contraceptive measures
•Be informed and understand the potential consequences of pregnancy and the need to notify her study doctor immediately if there is a risk of pregnancy
•Understand the need to commence lenalidomide as soon as it is dispensed following a negative pregnancy test
•Agree to use, two reliable forms of contraception simultaneously or practice complete abstinence (True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence [eg calendar, ovulation, symptothermal or post-ovulation methods] and withdrawal are not acceptable methods of contraception.) from heterosexual contact during the following time periods related to this study: 1) for at least 28 days before starting lenalidomid; 2) while taking lenalidomide; 3) during dose interruptions; and 4) for at least 28 days after thelast dose of lenalidomide.. The two methods of reliable contraception must include one highly effective method and one additional effective (barrier) method. If the below contraception methods are not appropriate for the FCBP, she must be referred to a qualified provider of contraception methods to determine the medically effective contraception method appropriate to the subject. The following are examples of highly effective and additional effective methods of contraception
•Examples of highly effective methods:
Intrauterine device (IUD)
Hormonal (birth control pills, injections, implants, levonorgestrel-releasing intrauterine system [IUS], medroxyprogesterone acetate depot injections, ovulation inhibitory progesterone-only pills [e.g. desogestrel])
Tubal ligation
Partner’s vasectomy
• Examples of additional effective methods:
Male condom
Diaphragm
Cervical Cap
• Agree to have two medically supervised pregnancy test with a minimum sensitivity of 25 mIU/ml prior to starting lenalidomide. The first pregnancy test must be performed within 10 to 14 days prior to the start of lenalidomide and the second pregnancy test must be performed within 24 hours prior to the start of lenalidomide. The subject may not receive lenalidomide until the study doctor has verified that the results of these pregnancy tests are negative. . This requirement also applies to women of childbearing potential who practice complete and continued abstinence.
• Agree to have a medically supervised pregnancy test weekly for the first 28 days of study participation and every 4 weeks while taking lenalidomide, at study discontinuation, and at day 28 following the last dose of lenalidomide. If menstrual cycles are irregular, the pregnancy testing must occur weekly for the first 28 days and then every 14 days whiletaking lenalidomide, at study discontinuation, and at days 14 and 28 following the last dose of lenalidomide. This requirement also applies to women of childbearing potential who practice complete and continued abstinence
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| E.4 | Principal exclusion criteria |
-Patients who require vitamin K antagonists except for low dose (INR ≤ 2,5)
-Known hypersensitivity to dexamethasone. Prior history of uncontrollable side effects to dexamethasone therapy.
-Active infection > grade 2 NCI-CTC version 3.0
-Known positive for HIV; active or chronic infectious hepatitis, type A, B or C infection (including patients who are tested anti-HBC positive and/or HBsAg positive) –serological testing for hepatitis A, B, C required
-Severe, unstable, or uncontrolled medical disease which would confound diagnoses or evaluations required by the protocol, including cardiac insufficiency (NYHA I –IV) uncontrolled diabetes, chronic hepatic or renal disease, active uncontrolled infection and chronic inflammatory intestinal disease, autoimmune diseases.
-Prior radiation therapy > 25% of bone marrow
-Regular blood transfusions
-Treatment with other experimental substances within 30 days before study start
-Participation in another clinical trial within 30 days before study start or during the trial
-Unwilling or unable to comply with the protocol
-Pregnant or lactating females.
-Patients with seizure disorders requiring medication (such as steroids or antiepileptics)
-Known hypersensitivity to one of the medications
-Patients with evidence or history of bleeding diathesis
-Patients undergoing renal dialysis
-Major surgery within 4 weeks prior to start of study or incomplete wound healing
-Drug or alcohol abuse
-Psychological or social conditions that may interfere with the patients participation in the study or evaluation of the study results
-Known (at time of entry) gastrointestinal disorder, including malabsorbtion or active gastric ulcer, present to the extent that it might interfere with oral intake and absorption of study medication
-Any previous or concurrent malignancy or any cancer unless curatively treated > 3 years prior to study entry except cervical carcinoma in situ or adequately treated basal cell carcinoma
-Neuropathy > Grade 2
- Patients with bladder cancer or bladder cancer in their medical history
- Macrohematuria of unknown origin
- Patients with risk factors for bladder cancer (such as exposure to aromatic amines or heavy tobacco smokers)
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase I: Occurrence of DLTs in the first 4 weeks of treatment
Phase II: Response rate to treatment. Response defined according to IMWG criteria |
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| E.5.2 | Secondary end point(s) |
-Time to progression (TTP)
- Time to partial response (TPR)
- Overall survival (OS)
- Quality of life
- Tolerability and safety |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
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| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 9 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
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