| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed/refractory (R/R) lymphoma or R/R chronic lymphocytic leukemia (CLL) previously treated with at least one systemic therapy |
|
| E.1.1.1 | Medical condition in easily understood language |
Cancer of the white blood cells which has returned or become resistant
to previous treatment with at least one chemotherapy drug. |
|
| 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 | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10029592 |
| E.1.2 | Term | Non-Hodgkin's lymphomas NEC |
| E.1.2 | System Organ Class | 100000004851 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Dose finding part (Phase 1):
- To assess the safety and tolerability of durvalumab when given in combination with lenalidomide and rituximab; ibrutinib; or bendamustine and rituximab to determine the recommended phase 2 dose (RP2D) of each combination in subjects with lymphoma or chronic lymphocytic leukemia (CLL)
Dose confirmation part (Phase 1):
- To assess the safety of durvalumab as monotherapy and when given in combination with lenalidomide and rituximab; ibrutinib; or bendamustine and rituximab at the RP2D in subjects with lymphoma or CLL
Dose expansion part (Phase 2):
- To evaluate the preliminary efficacy of durvalumab when given in combination with lenalidomide and rituximab; ibrutinib; or bendamustine and rituximab in subjects with lymphoma or CLL
Arm A is discontinued to enrollment of new subjects. Subjects already enrolled and treated in Arm A who are receiving clinical benefit, based on investigators discretion may continue study treatment after being reconsented. |
|
| E.2.2 | Secondary objectives of the trial |
Dose finding & confirmation parts (Phase 1):
- To make a preliminary assessment of antitumor activity of durvalumab as
monotherapy and when given in combination with lenalidomide and rituximab;
ibrutinib; or bendamustine and rituximab in subjects with lymphoma or CLL
Dose expansion part (Phase 2):
- To assess the safety of durvalumab when given in combination with lenalidomide and rituximab; ibrutinib; or bendamustine and rituximab in subjects with lymphoma or CLL
All parts (Phase 1/2):
- To characterize the pharmacokinetics (PK) of durvalumab as monotherapy and when given in combination
- To characterize the PK of lenalidomide and ibrutinib when given in combination with durvalumab
- To determine the pharmacodynamic effects of durvalumab as monotherapy
Arm A is discontinued to enrollment of new subjects. Subjects already enrolled and treated in Arm A who are receiving clinical benefit, based on investigators discretion may continue study treatment after being reconsented. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
ALL TREATMENT ARMS (Arm A is discontinued to enrollment of new
subjects)
1. Subject is ≥18 years of age and ≤80 years of age at the time of signing the ICF. Subjects >80 years of age may be included if they meet criteria defined in the protocol
2. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted
3. Subject is willing and able to adhere to the study visit schedule and other protocol requirements
4. Subject has histologically confirmed and documented eligible histologies as defined in the protocol
5. Subject has been previously treated with at least one prior systemic chemotherapy, immunotherapy or chemoimmunotherapy
6. Subject with high-risk CLL/SLL is defined by the presence of at least one of the following factors:
a. Complex karyotype
b. del(17p) abnormality
c. Mutated TP53
d. Ibrutinib- or other BTK-inhibitor failure or an inadequate tumor response which is less than partial response
e. Relapsed/progressive disease within 6 months of completing their last therapy which may include investigational drug
7. Subject is willing and able to undergo biopsy:
a. Subject with lymphoma is willing and able to undergo tumor/lymph node biopsy (incisional/excisional or multiple core needle)
o During the Screening Period
o Any time during Cycle 2 (strongly recommended)
o At the time of disease progression from subjects who have achieved objective
response (CR/PR) to study treatment
b. Subject with CLL is willing and able to undergo bone marrow biopsy during the Screening and Treatment Periods
Material from a fine needle aspiration is not acceptable
8. Subject who has documented active relapsed or refractory disease requiring therapeutic intervention
9. Subject who has measurable disease:
a. For subject with lymphoma, bi-dimensionally measurable disease on cross-sectional imaging by computed tomography with at least one nodal or extranodal lesion ≥2.0cm in its longest dimension
Note: A previously irradiated lesion is ineligible to be used as a measurable target lesion
b. For subject with CLL, in need of treatment as defined by IWCLL Guidelines for the Diagnosis and Treatment of CLL (Appendix I of protocol)
10. Subject who has performance status of 0, 1, or 2 on the ECOG scale
11. Subject who has life expectancy of greater than 6 months
12. Subject who fulfills the laboratory requirements outlined in Table 6 of the protocol
13. Female subject of childbearing potential who is sexually active with a male must:
a. Have 2 negative pregnancy tests as verified by the investigator prior to starting any IP therapy. They must agree to ongoing pregnancy testing during the course of the study, and after the last dose of any IP. This applies even if the subject practices true abstinence from heterosexual contact
b. Use effective methods (1 highly effective and 1 additional effective [barrier] method) of contraception from 28 days prior to starting durvalumab and must agree to continue using such precautions while taking durvalumab (including dose interruptions) and for 90 days after the last dose of durvalumab. Cessation of contraception after this point should be discussed with a responsible physician
The following are examples of highly effective and additional effective methods of contraception:
Highly effective methods (defined as one that results in a low failure rate rate [ie, less than 1% per year] when used consistently and correctly):
(i) Intrauterine device (IUD); See Protocol Section 8.2
ii) Hormonal (birth control pills, injections, implants, levonorgestrel-releasing
intrauterine system [IUS], medroxyprogesterone acetate depot injections,
ovulation inhibitory progesterone-only pills [eg, desogestrel])
(iii) Tubal ligation
(iv) Partner’s vasectomy
Additional effective methods:
(i) Male condom
(ii) Diaphragm
(iii) Cervical cap
Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk of infection at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics should be considered particularly in subjects with neutropenia
c. Agree to abstain from breastfeeding during study participation and for at least 90 days after the last dose of durvalumab
d. Refrain from egg cell donation while taking durvalumab and for at least 90 days after the last dose of durvalumab
14. Male subject who is sexually active with a female partner of childbearing potential must:
a. Use male condom plus spermicide (even if he has undergone a successful vasectomy)from starting dose of durvalumab (Cycle 1 Day 1) through 90 days after receipt of the last dose of durvalumab. True abstinence is acceptable only when this is in line with the preferred and usual lifestyle of nonsterilized male subject
b. Refrain from semen or sperm donation while taking durvalumab and for at least 90 days after the last dose of durvalumab
See protocol for inclusion criteria specific to Arms A, B & C |
|
| E.4 | Principal exclusion criteria |
ALL TREATMENT ARMS (Arm A is discontinued to the enrollment of new
subjects)
1. Subject who has known or suspected central nervous system or meningeal involvement by lymphoma
2. Subject who has other lymphoma histologies which are not listed on Table 3, Table 4, or Table 5 of the protocol
a. Subject has blastoid variants of MCL or MCL with blastoid transformation.
b. Dose Confirmation and/or Expansion Parts only:
-Transformed lymphoma or Richter’s transformation
-DLBCL histology other than: not otherwise specified or T-cell/histiocyte rich
3. Subject who has any histopathologic finding consistent with myelodysplastic syndrome on bone marrow studies
4. Subject who has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
5. Subject who has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study
6. Subject who has any condition that confounds the ability to interpret data from the study
7. Subject who has any uncontrolled inter-current illness as defined in the protocol
8. Subject who is concurrently enrolled in another clinical study, unless in a follow-up period or it is an observational study
9. Subject who has any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer treatment
10. Subject who has received:
a. Any systemic antilymphoma/leukemia therapy, or hematopoietic growth factors, blood or platelets transfusions within 14 days prior to the first dose of IP (ie, Cycle 1 Day 1) and/or
b. Any radioimmunotherapy within 3 months prior to the first dose of IP (ie, Cycle 1 Day 1)
11. Subject who has unresolved toxicities from prior anticancer therapy, defined as having not resolved to NCI CTCAE v4.03 ≤ Grade 1 with the exception of alopecia and laboratory values listed per the exclusion criteria. Subjects with irreversible toxicity that is not reasonably expected to be exacerbated by durvalumab or other investigational treatments may be included (eg, hearing loss) after consultation with the sponsor’s medical monitor
12. Subject who received any prior mAb against PD-1 or PD-L1 and/or any prior:
a. Arm A only: IMiDs (eg, lenalidomide, thalidomide)
b. Arm B only: ibrutinib or other BTK inhibitor
c. Arm C only: bendamustine (except dose level 1)
13. Subject who has history of organ transplant or allogeneic hematopoietic stem cell transplantation
14. Subject who has taken corticosteroids during the last week prior to the first dose of IP (ie, Cycle 1 Day 1), unless administered at a dose equivalent to ≤ 10 mg/day prednisone. See Protocol for exceptions
15. Subject who has received live, attenuated vaccine within 30 days prior to the first dose of durvalumab. (Note: Subjects, if enrolled, should not receive live vaccine during the study and for 12 months after last dose of rituximab or until recovery of B-cells and for 120 days after the last dose of durvalumab, whichever is longer)
16. Subject who has undergone major surgical procedure (as defined by the investigator) within 28 days prior to the first dose of the IP or still recovering from prior surgery
17. Subject who has active documented autoimmune disease prior to first dose of durvalumab; see Protocol for exceptions
18. Subject who has history of primary immunodeficiency or tuberculosis
19. Subject who has known seropositivity for or active infection for human immunodeficiency virus or hepatitis C virus
20. Subject who is seropositive for or active viral infection with hepatitis B virus (HBV)
a. HBV surface antigen (HBsAg) positive
b. HBV surface antigen (HBsAg) negative, HBV core antibody (anti-HBc) positive, and detectable viral DNA
21. Female subject who is pregnant, breastfeeding, or intend to become pregnant during the participation in the study
22. Subject who has other invasive malignancy within 2 years prior to signing the ICF except for noninvasive malignancies such as cervical carcinoma in situ, non-melanomatous carcinoma of the skin, ductal carcinoma in situ of the breast, or incidental histologic finding of prostate cancer (T1a or T1b using the TNM [tumor, nodes, metastasis] clinical staging system) that has/have been surgically cured
a. Arm A only: Subject who has history of other malignancies, unless the subject has been free of the disease for ≥ 5 years prior to signing the ICF
Exceptions: History of previously treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin and related localized non-melanoma skin cancer, carcinoma in situ of the cervix, carcinoma in situ of breast, incidental histologic finding of prostate cancer (T1a or T1b using the TNM clinical staging system)
23. Subject who has known allergy or hypersensitivity to the active substance or any of the excipients, or to other humanized mAbs
See protocol for exclusion criteria specific to Arms A, B & C |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Dose finding (Phase 1):
• Safety
Dose confirmation (Phase 1):
• Safety
Dose expansion (Phase 2):
• Preliminary efficacy
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
As outlined in the following tables in the protocol:
• Table 7: Table of Events – Arm A - Durvalumab and Lenalidomide ± Rituximab (This arm is discontinued to enrollment of new subjects; the procedures apply to continuing subjects in the study)
• Table 8: Table of Events – Arm B - Durvalumab and Ibrutinib
• Table 9: Table of Events – Arm C – Durvalumab and Rituximab ± Bendamustine
• Table 10: Table of Events – Arm D – Durvalumab Monotherapy |
|
| E.5.2 | Secondary end point(s) |
Dose finding and confirmation (Phase 1):
• Preliminary antitumor activity (IWG Response Criteria for Malignant Lymphoma & IWCLL Response Criteria for CLL)
All parts (Phase 1/2):
• Other efficacy parameters (IWG Response Criteria for Malignant &
IWCLL Response Criteria for CLL)
• Time to first response (TTR)
• Duration of response (DoR)
• Progression-free survival (PFS)
Dose expansion (Phase 2):
• Safety
All parts (Phase 1/2):
• PK
• Pd
See Table 2 of the protocol for further detail. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
As outlined in the following tables in the protocol:
• Table 7: Table of Events – Arm A - Durvalumab and Lenalidomide ± Rituximab (This arm is discontinued to enrollment of new subjects; the procedures apply to continuing subjects in the study)
• Table 8: Table of Events – Arm B - Durvalumab and Ibrutinib
• Table 9: Table of Events – Arm C – Durvalumab and Rituximab ± Bendamustine
• Table 10: Table of Events – Arm D – Durvalumab Monotherapy |
|
| 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 | No |
| 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 | Yes |
| E.6.10 | Pharmacogenetic | No |
| 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) | 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 |
| Dose finding and dose confirmation |
|
| 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 | No |
| 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) | 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 | 4 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 44 |
| 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 |
| Canada |
| France |
| Germany |
| Italy |
| Japan |
| Netherlands |
| United Kingdom |
| United States |
|
| 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
|
| The End of Trial is defined as either the date of the last visit of the last subject to complete the post-treatment follow-up, or the date of receipt of the last data point from the last subject that is required for primary, secondary, and/or exploratory analysis, as prespecified in the protocol, whichever is the later date. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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