| 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 |
| Non-Hodgkin’s Lymphoma is a group of blood cancers that includes all types of lymphoma except Hodgkin's lymphomas. Lymphomas are types of cancer that develop from lymphocytes -type of white blood cell |
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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 | 20.0 |
| E.1.2 | Level | HLGT |
| E.1.2 | Classification code | 10025322 |
| E.1.2 | Term | Lymphomas non-Hodgkin's unspecified histology |
| E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
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| 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 |
| To assess the efficacy of (1) umbralisib alone, (2) umbralisib plus ublituximab, and in select NHL subtypes, (3) umbralisib plus ublituximab plus bendamustine as measured by Overall Response Rate (ORR) |
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| E.2.2 | Secondary objectives of the trial |
SECONDARY OBJECTIVES
- To assess the efficacy of (1) umbralisib alone, (2) umbralisib plus ublituximab, and in select NHL subtypes, (3) umbralisib plus ublituximab plus bendamustine as measured by Progression-Free Survival (PFS) and Duration of Response (DOR)
- To assess safety, tolerability and other efficacy outcomes.
- To analyze population pharmacokinetics and any other potential drug-drug interactions of ublituximab and umbralisib
EXPLORATORY OBJECTIVES
- To observe the impact of cell of origin, mutational status, and select other biomarkers on efficacy of the umbralisib and the ublituximab + umbralisib combination in subjects with DLBCL
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet all the following inclusion criteria to be eligible for participation in this study:
1. Histologically confirmed diagnosis of: B-cell NHL with histological subtype limited to the following based on criteria established by the World Health Organization (WHO) 2008 classification of tumors of hematopoietic and lymphoid tissues:
a. Follicular Lymphoma (FL) of Grade 1, 2, or 3a;
b. Marginal Zone Lymphoma (MZL) (splenic, nodal, or extranodal); or
c. Mantle Cell Lymphoma (MCL) – with documentation of either overexpression of cyclin D1 or t(11;14).
d. Note: Subjects with Diffuse Large B-Cell Lymphoma (DLBCL) and Small Lymphocytic Lymphoma (SLL) were previously eligible, however new subject enrollment for these subtypes was closed in protocol V5.0.
e. As of protocol V6.0 – Small Lymphocytic Lymphoma (SLL) subjects are eligible for enrollment
2. Treatment status:
a. As of Protocol V6.0 – FL, SLL and MZL subjects - Treatment naïve or previously treated with a maximum of two prior lines of therapy (excluding antibiotics); FL subjects must have documented evidence for requiring treatment (one or more of the following: bulky disease (>5 cm), high LDH, B symptoms, threatened organ function, splenomegaly, cytopenias due to lymphoma, or effusions;
b. Protocol V3.0 - V5.1 (closed) - FL subjects: relapsed or refractory after ≥ 2 prior lines of systemic therapy. Subjects must have received an anti-CD20 mAb and an alkylating agent, and must have documented evidence for requiring treatment (one or more of the following: bulky disease (>5 cm), high LDH, B symptoms, threatened organ function, splenomegaly, cytopenias due to lymphoma, or effusions);
c. Protocol V2.0 - V5.1 (closed) - MZL subjects: prior treatment with one or more lines of therapy including at least one CD20-directed regimen (either as monotherapy or as chemoimmunotherapy) with documented failure to achieve at least PR or documented PD after the most recent systemic treatment regimen, and must have documented evidence for requiring treatment (one or more of the following: bulky disease (>5 cm), high LDH, B symptoms, threatened organ function, splenomegaly, cytopenias due to lymphoma, or effusions);
d. Protocol V4.0 – V6.0 - MCL subjects: prior treatment with one or more lines of therapy including at least one BTK inhibitor (either ibrutinib, acalabrutinib or zanibrutinib only) with documented failure to achieve at least PR or documented PD during, or within 6 months of discontinuing, prior BTK therapy;
3. Measurable disease, defined as at least 1 measurable disease lesion > 1.5 cm in at least one diameter by CT/CT-PET or magnetic resonance imaging (MRI) in an area of no prior radiation therapy, or in an area that was previously irradiated that has documented progression.
4. Adequate organ system function, defined as follows:
a. Absolute neutrophil count (ANC) > 1,000/mm3 (µL) & platelet count > 50,000/mm3 (µL)
b. Total bilirubin ≤ 1.5 times the upper limit of normal (ULN)
c. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN if no liver involvement or ≤ 5 x the ULN if known liver involvement
d. Calculated creatinine clearance ≥ 30 mL/min (as calculated by the Cockcroft-Gault formula)
5. ECOG performance status ≤ 2
6. Male or female ≥ 18 years of age
7. Ability to swallow and retain oral medication
8. Female subjects who are not of child-bearing potential (see Appendix B- Contraceptive Guidelines and Pregnancy), and female subjects of child-bearing potential who have a negative serum pregnancy test within 3 days prior to Cycle 1, Day 1. Female subjects of child-bearing potential, and male partners must consent to use a medically acceptable method of contraception throughout the study period and for 4 months after the last dose of either study drug.
9. Willingness and ability to comply with trial and follow-up procedures, and give written informed consent
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| E.4 | Principal exclusion criteria |
Subjects who meet any of the following exclusion criteria are not to be enrolled to this study:
1. Subjects receiving cancer therapy (i.e., chemotherapy, radiation therapy, immunotherapy, biologic therapy, hormonal therapy, surgery and/or tumor embolization) or any investigational drug within 21 days of Day 1 of Cycle 1.
a. Corticosteroid therapy started at least 7 days prior to study entry (prednisone ≤10 mg daily or equivalent) is allowed as clinically warranted. Topical or inhaled corticosteroids are permitted.
b. Palliative radiation therapy is allowed as clinically warranted.
2. Subjects who have received autologous hematologic stem cell transplant within 6 months of study entry. Prior allogeneic hematologic stem cell transplant is excluded.
3. Evidence of chronic active Hepatitis B (HBV) as evidenced by a detectable hepatitis B surface antigen (not including subjects with prior hepatitis B vaccination); or positive serum Hepatitis B surface antibody) or chronic active Hepatitis C infection (HCV), cytomegalovirus (CMV), or known history of HIV. If HBc antibody, HCV antibody or CMV IgG or IgM is positive the subject must be evaluated for the presence of HBV DNA, HCV RNA, or CMV DNA by PCR - See Appendix D – Hepatitis B Serologic Test Results.
4. Known history of Central Nervous System (CNS) lymphoma; subjects with symptoms of CNS disease must have a negative MRI scan and negative diagnostic lumbar puncture.
5. Known histological transformation from chronic lymphocytic leukemia to large cell lymphoma (i.e. Richter’s transformation)
6. Evidence of ongoing systemic bacterial, fungal or viral infection, except localized fungal infections of skin or nails.
7. History of anaphylaxis (excluding infusion related reactions) in association with previous anti-CD20 administration (for subjects eligible to enroll to an ublituximab containing regimen only).
8. Prior exposure to idelalisib (CAL-101), duvelisib (IPI-145), copanlisib or any other drug that specifically inhibits phosphoinositide-3-kinase (PI3K)
9. Any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:
a. Symptomatic, or history of documented congestive heart failure (NY Heart Association functional classification III-IV [See Appendix C – NYHA Classifications])
b. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of randomization
c. Concomitant use of medication known to cause QT prolongation or torsades de pointes should be used with caution and at investigator discretion.
d. Poorly controlled or clinically significant atherosclerotic vascular disease including cerebrovascular accident (CVA), transient ischemic attack (TIA), angioplasty, cardiac/vascular stenting within 6 months of enrollment
10. Malignancy within 3 years of study enrollment except for adequately treated basal, squamous cell carcinoma or non-melanomatous skin cancer, carcinoma in situ of the cervix, superficial bladder cancer not treated with intravesical chemotherapy or BCG within 6 months, localized prostate cancer and PSA < 1.0 mg/dL on 2 consecutive measurements at least 3 months apart with the most recent one being within 4 weeks of study entry.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy Endpoints
Overall response rate (ORR)
ORR is defined as sum of CR and PR rates.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| During the study period, all subjects will be evaluated for response by CT, PET-CT and/or MRI at the end of Cycle 3 and then within 14 days prior to Day 1 of Cycles 6, 9, and 12. After Cycle 12, response assessments should occur every 6 cycles or more frequently as clinically indicated. All baseline assessments to characterize disease will be performed within 30 days of Cycle 1 Day 1, prior to initiation of therapy. During the treatment period, all efficacy assessments have a +/- 14 day window. |
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| E.5.2 | Secondary end point(s) |
Progression-free survival (PFS) at Month 6
PFS at Month 6 is defined as the percent of subjects not experiencing progression (i.e., definitive disease progression or death from any cause) by Month 6.
Progression-free survival (PFS)
PFS is defined as the interval from randomization to the earlier of the first documentation of definitive disease progression or death from any cause. Definitive disease progression based on standard criteria (Cheson et al., 2007).
Complete Response (CR) Rate
CR rate is defined as the proportion of subjects who achieve a CR.
Overall survival (OS)
OS is defined as the interval from randomization to death from any cause
Duration of Response (DOR)
Duration of response is defined as the time from documentation of a response to treatment to the first documentation of tumor progression or death due to any cause, whichever comes first.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| During the study period, all subjects will be evaluated for response by CT, PET-CT and/or MRI at the end of Cycle 3 and then within 14 days prior to Day 1 of Cycles 6, 9, and 12. After Cycle 12, response assessments should occur every 6 cycles or more frequently as clinically indicated. All baseline assessments to characterize disease will be performed within 30 days of Cycle 1 Day 1, prior to initiation of therapy. During the treatment period, all efficacy assessments have a +/- 14 day window |
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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 | Yes |
| 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) | 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 | Yes |
| 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 | 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 27 |
| 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 |
| Australia |
| Israel |
| Korea, Republic of |
| United States |
| Italy |
| Poland |
| Slovakia |
| United Kingdom |
| Spain |
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| 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 | 6 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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