| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Relapsed or refractory follicular lymphoma (FL) or marginal zona lymphoma (MZL)
|
|
| E.1.1.1 | Medical condition in easily understood language |
| Follicular lymphoma is a type of blood cancer. It is the most common of the indolent (slow-growing) non-Hodgkin's lymphomas, and the second-most-common form of non-Hodgkin's lymphomas overall. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 24.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10029473 |
| E.1.2 | Term | Nodular (follicular) lymphoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10076596 |
| E.1.2 | Term | Marginal zone lymphoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
Primary Objective
• To demonstrate that zandelisib in combination with R is superior to standard immunochemotherapy in prolonging PFS as determined by the Independent Response Review Committee (IRRC) in previously treated subjects with follicular and marginal zone lymphoma |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives
• To compare zandelisib + R to standard immunochemotherapy by ORR and complete response rate (CRR) as determined by the IRRC
• To compare zandelisib + R to standard immunochemotherapy by overall survival (OS)
• Time to next anti-lymphoma treatment (TTNT)
• Progression-free survival on next anti-lymphoma treatment (PFS2)
• To evaluate Patient Reported Outcomes (PRO) with FlymSI-18 and EuroQol 5 Dimension 3-Level (EQ-5D-3L)
• To evaluate the safety and tolerability of zandelisib in combination with R |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female subjects ≥18 years of age, ≥19 years in Korea, or ≥20 years for subjects in Japan and Taiwan, at time of signing informed consent
2. Histologically confirmed diagnosis of CD20 positive iNHL with histological subtype limited to:
a. FL Gr 1, Gr 2, or Gr 3a
b. MZL (splenic, nodal, or extra-nodal)
[Histopathological report confirming diagnosis must be available during screening procedures]
3. Subjects with relapsed or refractory disease who received ≥1 prior lines of therapy that must have included an anti-CD20 antibody in combination with cytotoxic chemotherapy or L, with or without subsequent maintenance therapy. [A line of therapy is defined as following: a minimum of 2 consecutive cycles of immunochemotherapy or R-L, at least 4 doses of anti-CD20 mAb (R) single agent therapy a minimum of 2 consecutive cycles of therapy with an investigational agent. Maintenance therapy given after an induction treatment (e.g., R maintenance) is considered as the same line of therapy]. [Please seeExclusion Criteria #2 for further clarification]. Relapsed or refractory disease defined as:
• Relapsed disease: disease progression after a response (complete response [CR] or partial response [PR]) lasting ≥6 months
• Refractory disease: no response to therapy (no CR or PR) or response lasting <6 months
4. Subjects must have at least one bi-dimensionally measurable nodal lesion with the longest diameter >1.5 cm and/or an extranodal lesion >1.0cm (that has not been previously irradiated) according to the Lugano Classification
5. Adequate hematologic parameters at screening unless abnormal values are due to disease per Investigator assessment:
• Absolute neutrophil count (ANC) ≥1.0 × 109/L (≥1,000/mm3)
• Platelet count ≥75.0 × 109/L (≥75,000/mm3)
• Hemoglobin ≥9 g/dL
6. Adequate renal and hepatic function per local laboratory reference range at screening as follows:
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤1.5 × upper limit of normal (ULN)
• Total bilirubin ≤2.0 × ULN or ≤3 × ULN for subjects with Gilbert-Meulengracht syndrome
• Estimated glomerular filtration rate (eGFR) >50 mL/min using the Cockcroft-Gault equation (Appendix 2)
7. QT-interval corrected according to Fridericia’s formula (QTcF) ≤450 msec; subjects with QTc >450 msec but <480 msec may be enrolled provided the QTc prolongation is due to a right bundle branch block (RBBB), left bundle branch block (LBBB), or pacemaker and is confirmed stable by a cardiologist.
8. Left ventricular ejection fraction (LVEF) ≥45% as measured by echocardiogram (ECHO) or multi-gated acquisition scan. [If LVEF <45% by ECHO, a repeat measurement can be conducted within the screening period.]
9. Subjects must have completed any prior systemic anti-cancer treatment ≥4 weeks (or ≥5 times the half-life [t½] of used therapeutics [including investigational therapy], whichever is longer) or radiation therapy ≥2 weeks before study D1, and ≥3 months before study D1 for high dose therapy with stem cell transplantation, radioimmunotherapy, and CAR T-cell therapy.
10. Eastern Cooperative Oncology Group (ECOG) performance status 0-1
11. Life expectancy of at least 3 months
12. All AEs and laboratory toxicities related to prior therapy must resolve to Gr ≤1 prior to the start of the study therapy (unless otherwise specified in eligibility criteria)
13. For females of childbearing potential, a negative serum human chorionic gonadotropin (hCG) pregnancy test within 28 days of study D1 and negative result (urine or serum) on study D1
14. Subjects must agree to use appropriate contraception methods during the clinical study (Appendix 3)
15. Subject is willing and able to comply with all scheduled visits, treatment plans, laboratory tests, and other study procedures |
|
| E.4 | Principal exclusion criteria |
1. Histologically confirmed diagnosis of FL Gr 3b or transformed disease
• For subjects with clinical signs of rapid disease progression (e.g., marked B-symptoms), and laboratory or radiographic indication (e.g., high lactate dehydrogenase level or standardized uptake value by PET), a fresh tumor biopsy is recommended to rule out transformed disease
2. Subjects who received both R/O-B and R/O-CHOP (or other anthracycline-containing regimen) as previous lines of therapy, and those who received only single agent anti-CD20 mAb therapy as prior line of treatment
3. Prior therapy with PI3K inhibitors
4. Ongoing or history of drug-induced pneumonitis
5. Known lymphomatous involvement of the central nervous system
6. Seropositive for or active viral infection with hepatitis B virus:
• HBsAg positive
• HBsAg negative, anti-HBs positive and/or anti-HBc positive and detectable viral DNA by PCR
[Note: Subjects who are HBsAg negative and viral DNA PCR negative are eligible. These subjects should receive prophylactic therapy for hepatitis as per institutional standards.]
7. Known seropositive for, or active infection with hepatitis C virus.
• Subjects with positive hepatitis C virus (HCV) antibodies are eligible with negative PCR test for HCV
8. Known seropositive for, or active and uncontrolled infection with human immunodeficiency virus (HIV), or with acquired
immunodeficiency syndrome (AIDS), or currently taking medications for HIV that are contraindicated for concomitant use in this study
9. Known seropositive for, or active infection with human T-cell leukemia virus type 1
10. Any uncontrolled clinically significant illness including, but not limited to, active infections requiring systemic antimicrobial therapy, hypertension, angina, arrhythmias, or other uncontrolled cardiovascular conditions, pulmonary disease, or autoimmune dysfunction, and urinary infection or flow obstruction
11. Hypersensitivity or other clinically significant reaction to the study drug or its inactive ingredients or other therapy used in the study
12. Major surgical procedure within 4 weeks prior to study D1 (minor surgical procedures, e.g., lymph node biopsy, performed within 1 day or with an overnight stay are allowed)
13. Previous or concurrent cancer that is distinct in primary site or histology from indolent B cell NHL within 3 years before start of study treatment except for curatively treated cervical cancer in situ, non-melanoma skin cancer, and superficial bladder tumors (Ta [non-invasive tumor], Tis [carcinoma in situ], and T1 [tumor invades lamina propria]), and asymptomatic localized prostate cancer with no requirement for systemic therapy or requiring only hormonal therapy and with normal prostate-specific antigen values within ≥12 months prior to randomization
14. History of clinically significant cardiovascular abnormalities such as congestive heart failure (New York Heart Association (NYHA) classification ≥ II
[NYHA 1994]), myocardial infarction within 6 months of study entry.
15. History of clinically significant gastrointestinal (GI) conditions, particularly:
• Known GI condition that would interfere with swallowing or the oral absorption or tolerance of study drug
• Pre-existing malabsorption syndrome or other clinical situation that would affect oral absorption
16. Females who are pregnant; females who plan to breastfeed during study treatment through 90 days after ending treatment
17. Substance abuse, medical, psychological or social conditions that may interfere with the subject’s participation in the study or evaluation of the study results.
18. Any illness or medical conditions that are unstable or could jeopardize the safety of the subjects and their compliance in the study. Inability to understand and sign informed consent form.
19. Received a live virus vaccination within 28 days of first dose of study drug, (e.g., yellow fever vaccination). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PFS as determined by the IRRC |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The study duration for primary completion of PFS is approximately 64 months with 36 months enrollment period and 28 months follow-up (after last subject enrolled). |
|
| E.5.2 | Secondary end point(s) |
• Efficacy: ORR and CRR as determined by the IRRC
• OS
• TTNT
• PFS2
• PRO – time to deterioration in the 9-item DRS-P subset of FlymSI-18
• PRO – time to improvement in the 9-item DRS-P subset of FlymSI-18
• PRO - functional and well-being (FWB) score and change from baselinein the DRS-P and FWB subscales and total score of FlymSI-18 at specified study visits
• PRO – change from baseline in EQ-5D-3L total score and VAS score at specified study visits
• Treatment-emergent AEs, serious AEs, and laboratory abnormalities
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Please refer to study 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 | 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) | 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| 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) | Yes |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 65 |
| 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 |
| Georgia |
| Puerto Rico |
| Serbia |
| Turkey |
| Argentina |
| Belgium |
| Canada |
| China |
| Germany |
| Greece |
| Hungary |
| Ireland |
| Italy |
| Japan |
| Korea, Republic of |
| Netherlands |
| Poland |
| Russian Federation |
| Spain |
| Taiwan |
| Ukraine |
| United Kingdom |
| United States |
| France |
|
| 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 study will end when all subjects have been followed for survival, or lost to follow up, or 5 years from the last subject’s randomization, whichever comes first |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
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