| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 10008976 |
| E.1.2 | Term | Chronic lymphocytic leukemia |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003910 |
| E.1.2 | Term | B-cell small lymphocytic lymphoma NOS |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
| To determine the safety of MOR00208 combined with idelalisib or venetoclax. |
|
| E.2.2 | Secondary objectives of the trial |
1. To determine the quality of the response
2. To assess the potential immunogenicity of MOR00208
3. To assess the pharmacokinetic (PK) profile of MOR00208
|
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Optional Sub-Study - Collection of Biological Samples for Evaluation of CD19 Expression after MOR00208 Treatment
The sub-study is contained within Section 15.13 (Appendix M) of the main MOR208C205 study protocol.
Study Objectives:
• To assess potential downregulation/loss of CD19 on peripheral B cells (CLL and normal B cells) as escape mechanism to MOR00208 treatment
• To assess the kinetics of CD19 recovery on peripheral B cells (CLL and normal B cells) after MOR00208 treatment discontinuation, if applicable
• To assess MOR00208 serum concentrations as supportive parameter for CD19 expression analysis |
|
| E.3 | Principal inclusion criteria |
Diagnosis/Trial Population
1. Age ≥18 years
2. Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL):
a) history of diagnosis of CLL or SLL that meets IWCLL diagnostic criteria (Hallek et al., 2008)
b) histologically confirmed diagnosis of SLL by lymph node biopsy and documented within medical records
c) indication for treatment as defined by the IWCLL guidelines (Hallek et al., 2008)
3. Patients must have both of the following:
a) relapsed (1) or refractory (2) disease while receiving a BTK inhibitor (e.g., ibrutinib) or intolerance of such therapy
b) single-agent or combination therapy with a BTK inhibitor for at least one month must be the patient’s most recent prior anticancer therapy
(1) relapsed disease is defined as progressive disease in subjects who have previously achieved a PR or CR to most recent BTK inhibitor therapy
(2) refractory disease is defined as progressive disease in subjects who have previously not achieved a PR or CR to most recent BTK inhibitor therapy, or stable disease as best response after 12 months of receiving the most recent BTK inhibitor therapy
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
5. Patients with a past medical history of autologous or allogeneic stem cell transplantation must exhibit full hematological recovery without any evidence or ongoing treatment of active graft versus host disease before enrolment into the study.
Laboratory Values
6. Patients must meet the following laboratory criteria at screening:
•adequate bone marrow function as follows:
a) absolute neutrophil count (ANC) ≥ 1.0 × 109/L
b) platelet count ≥ 30 × 109/L in the absence of clinically significant evidence of bleeding
c) Cohort B only: hemoglobin ≥ 8.0 g/dL
• Adequate hepatic and renal function as follows:
d) total serum bilirubin ≤ 1.5 × ULN or ≤ 3 × ULN in cases of documented liver involvement by CLL (For patients with Gilbert’s disease, serum bilirubin up to 3 × ULN is allowed provided normal direct bilirubin.)
e) ALT and AST ≤ 2.5 × ULN or <3 ×ULN in cases of documented liver involvement by CLL
f) serum creatinine clearance calculated using a standard Cockcroft-Gault formula (Cockroft & Gault, 1976) must be:
• Cohort A only: ≥ 30 mL/min
• Cohort B only: ≥ 50 mL/min
Other Inclusion Criteria
7. Females of childbearing potential (FCBP; see Appendix F of the protocol) must:
a) not be pregnant as confirmed by a negative serum pregnancy test at screening and a urine pregnancy test prior to starting study therapy
b) refrain from breastfeeding and donating blood or oocytes during the course of the study and for 3 months after the last dose of study medication (Note: All female patients are prohibited to donate blood within the before mentioned time frame)
c) agree to ongoing pregnancy testing during the course of the study, and until 3 months after study therapy has ended. This applies even if the patient practices complete and continued sexual abstinence
d) commit to continued abstinence from heterosexual intercourse if it is in accordance with her lifestyle or agree to use and be able to comply with the use of highly effective contraception (see Appendix F of the protocol) without interruption during the study and for 3 months after the last dose of study medication
e) FCBP using hormonal contraceptives should add a barrier method as a second form of contraception since it is currently unknown whether idelalisib or venetoclax may affect the effectiveness of hormonal contraceptives
8. Males must use a highly effective method of contraception (see Appendix F of the protocol) without interruption, if the patient is sexually active with a FCBP, refrain from donating blood or sperm during the study participation and for 3 months after the last dose of study medication
9. In the opinion of the Investigator the patients must:
a) be able to understand, give written informed consent to, and comply with all study-related procedures, medication use, and evaluations
b) not have a history of noncompliance in relation to medical regimens or be considered potentially unreliable and/or uncooperative |
|
| E.4 | Principal exclusion criteria |
Diagnosis
1. Patients who have:
a) non-Hodgkin’s lymphomas other than CLL/SLL
b) transformed CLL/SLL or Richter’s syndrome as defined by the IWCLL
c) active and uncontrolled autoimmune cytopenia
Previous and Current Treatment
2. Patients who have received treatment with a BTK inhibitor within 5 days prior to Day 1 dosing.
3. Patients who have, within 14 days prior to Day 1 dosing:
a) not discontinued CD20-targeted therapy, chemotherapy, radiotherapy, investigational anticancer therapy or other lymphoma-specific therapy
b) systemic corticosteroids in doses greater than prednisone equivalent to 20 mg/day
c) received live vaccines.
4. Patients who:
a) have, in the opinion of the Investigator, not recovered sufficiently from the adverse toxic effects of prior therapies
b) have a history of previous severe allergic reactions to prior monoclonal antibody therapy, and/or hypersensitivity to the active substances or to any of the inactive ingredients / excipients contained in the study drug formulations
c) concurrently use other anticancer or experimental treatments
d) were previously treated with:
• CD19-targeted therapy (applicable for Cohort A and B)
• Cohort A only: a PI3K inhibitor treatment (e.g., idelalisib, duvelisib)
• Cohort B only: a BCL-2 inhibitor treatment (e.g., venetoclax)
e) Cohort B only: has a known allergy to both xanthine oxidase inhibitors and rasburicase
f) Cohort B only: has received strong or moderate CYP3A inhibitors or inducers within 7 days, or has consumed grapefruit, grapefruit products, Seville oranges or star fruit within 3 days prior to the first dose of venetoclax
Patient’s Medical History
5. Prior history of malignancies other than CLL, unless the patient has been free of the disease for ≥5 years prior to screening. Exceptions to the ≥5 year time limit include a history of the following:
a) basal cell carcinoma of the skin
b) squamous cell carcinoma of the skin
c) carcinoma in situ of the cervix
d) carcinoma in situ of the breast
e) carcinoma in situ of the bladder
f) incidental histological finding of prostate cancer (Tumor/Nodes/Metastasis [TNM] stage of T1a or T1b)
6. Patients with myelodysplastic syndrome
7. Patients with systemic diseases (e.g., cardiovascular, renal, hepatic) that would in the Investigator’s opinion preclude participation in the study or compromise the patient’s ability to give informed consent
8. Patients with diagnosis of myocardial infarction within 6 months prior to enrolment, New York Heart Association class II or higher congestive heart failure, uncontrolled angina pectoris, severe uncontrolled ventricular arrhythmias, clinically significant pericardial disease, or electrocardiographic evidence of acute ischemia or significant conduction system abnormalities, in the opinion of the Investigator. (Note: Patients with stable, asymptomatic atrial fibrillation are allowed in the study provided they do not meet the other cardiac exclusion criteria)
9. Patients who:
a) suffered significant traumatic injury or underwent major surgery within 14 days prior to treatment start
b) have not recovered from sequelae of traumatic injury or surgical operations until Day 1 dosing
10. Patients with central nervous system (CNS) involvement or impairment:
a) CNS primary or secondary malignancy in present or past medical history (unless patient has been free of the disease for ≥ 5 years prior to screening) (1)
b) CNS, meningeal or epidural malignancies (e.g., brain metastases, known leukemic meningeosis) (1)
(1) Note: Screening for cerebrospinal fluid (CSF)/CNS involvement is not required but may be performed at the discretion of the Investigator
c) CNS lesions/cerebrovascular event(s) with clinically significant sequelae
d) history or evidence of clinically significant cerebrovascular CNS that would in the Investigator’s opinion preclude participation in the study or compromise the patient’s ability to give informed consent.
11. Patients with:
a) chronic diarrhoea and malabsorption syndrome
b) any evidence of ongoing systemic viral, bacterial, or fungal infection (including Pneumocystis jirovecii pneumonia and Cytomegalovirus infection)
c) history of serious allergic reactions including anaphylaxis and toxic epidermal necrolysis
d) Cohort A only: ongoing inflammatory bowel disease as ulcerative colitis or Crohn’s disease
e) Cohort A only: severe COPD, or pulmonary emphysema or drug-induced pneumonitis diagnosed in previous medical history
12. Patients with known seropositivity for or history of active viral infection with HIV.
13. Patients with known positive hepatitis B and/or C serology
a) HBV: patients with positive serology for HBV. (Note: Patients positive for anti-HBc may be included if HBV DNA is not detectable, but have to be monitored in 2-month intervals via HBV DNA testing)
b) HCV: patients with positive HCV serology unless confirmed negative for HCV-ribonucleic acid (RNA) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Incidence and severity of adverse events (AEs) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Please refer to Section 9.1 Schedule of Procedures and Assessments of the Protocol. |
|
| E.5.2 | Secondary end point(s) |
1. Overall response rate (ORR): defined for Cohort A as percentage of
patients achieving a complete response (CR), a partial response (PR) or a partial response with lymphocytosis (PRL), and for Cohort B as
percentage of patients achieving a CR or a PR
2. Anti-MOR00208 antibody formation
3. Pharmacokinetic analysis for MOR00208
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Please refer to Section 9.1 Schedule of Procedures and Assessments of the Protocol. |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| 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 | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Austria |
| Germany |
| Italy |
| Poland |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
The end of the main study is defined as 5 years after the first patient was enrolled (Cycle 1, Day 1) or approximately 30 days after last patient received his last treatment, whichever comes first.
The sub-study will be completed once the last patient in the sub-study completed the last visit, or approximately 7 months after the first visit of the last patient enrolled in the sub-study, whichever comes first.
The whole study will end after the completion of both the main and sub-study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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