| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Indolent B-Cell Non-Hodgkin Lymphoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Non-Hodgkin Lymphoma (cancer) |
|
| 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 | 10025320 |
| E.1.2 | Term | Lymphomas non-Hodgkin's B-cell |
| E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
|
| 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 |
•Assess the safety and tolerability profile of BI-1206 when administered intravenously (IV) or subcutaneously (SC) in combination with rituximab or rituximab and acalabrutinib in subjects with relapsed or refractory B- cell non-Hodgkin lymphoma (NHL), subtypes follicular lymphoma (FL)
(except FL grade 3B), marginal zone lymphoma (MZL), and mantle cell lymphoma (MCL).
Phase 1:
•Select the recommended Phase 2 dose (RP2D) by establishing the maximum tolerated dose (MTD) of BI-1206 administered via IV infusion or SC injection in combination with rituximab.
Phase 2a, BI-1206 in Combination with Rituximab and Acalabrutinib:
•Selection of recommended ose of BI-1206 in combination with rituximab and acalabrutinib.
|
|
| E.2.2 | Secondary objectives of the trial |
•Study the pharmacokinetic (PK) profile of BI-1206 when administered IV or SC in combination with rituximab or rituximab and acalabrutinib in subjects with relapsed or refractory B-cell NHL, subtypes FL (except FL grade 3B), MZL and MCL.
•Assess the immunogenicity of BI-1206 when administered IV or SC in combination with rituximab or rituximab and acalabrutinib.
•Evaluate the effect of BI-1206 administered IV or SC in combination with rituximab or rituximab and acalabrutinib on the depletion of B-cells.
•Assess possible anti-tumor activity of BI-1206 administered IV or SC in combination with rituximab or rituximab and acalabrutinib at Week 6, and for subjects who continue during maintenance therapy.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Are ≥ 18 years of age by initiation of study treatment.
2. Provide written (signed and dated) informed consent.
3. Are capable of cooperating with treatment and follow-up.
4. Have B-cell NHL proven by histology, with histological subtypes limited to FL (except FL3B), MCL and MZL.
5. Have measurable nodal disease, defined as the presence of ≥1 nodal lesion that measures ≥1.5 cm in a single dimension as assessed by computerized tomography (CT) or magnetic resonance imaging (MRI).
6. Are willing to undergo lymph node biopsies or biopsies of other involved tissue (besides bone marrow). However, if a biopsy is not technically feasible, the sample can be omitted. If viable frozen tissue (not formalin-fixed) from a previous standard of care biopsy in the previous 8 weeks prior to consent is available, a new biopsy at screening is not required.
7. Have relapsed disease or disease refractory to conventional treatment or for which no standard therapy exists, the investigator judges available standard therapy as not being appropriate for the subject, or is declined by the subject. Rituximab refractory disease is defined as:
• Lack of CR or PR during rituximab-containing treatment comprising ≥2 doses of ≥375 mg/m2, or
• Occurrence of progressive disease up to one year after completion of a regimen of rituximab-containing therapy comprising ≥2 doses of ≥375 mg/m2, or
• Occurrence of progressive disease during rituximab maintenance therapy or within 6 months of completion of rituximab maintenance therapy.
8. Have received at least one line of conventional previous therapy which must include at least one rituximab-based regimen.
9. Have a life expectancy of at least 12 weeks on the day of the first infusion of BI-1206.
10. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2.
11. Have CD20+ malignancy as demonstrated by IHC or flow cytometry prior to first dose of BI-1206. Analysis must have been performed on the most recent biopsy obtained and must be after anti-CD20 therapy.
12. Have hematological and biochemical indices within prespecified ranges, including hemoglobin (≥9.0 g/dL, red cell support is permissible); absolute neutrophil count (ANC) (≥1.0 × 109/L, or >0.5 × 109/L if due to lymphoma; granulocyte-colony stimulating factor support is not permissible at screening); and platelet count (≥100 × 109/L). These measurements must be performed within 1 week and assessed by the Investigator before their first dose of BI-1206. |
|
| E.4 | Principal exclusion criteria |
1. Have had an allogenic bone marrow or stem cell transplant within 12 months prior to the first dose of BI-1206.
2. Have presence of active chronic graft versus host disease of any grade/severity.
3. Have current leptomeningeal lymphoma or compromise of the central nervous system.
4. Have transformed lymphoma from a pre-existing indolent lymphoma. Subjects with a previous history of transformation, but on this disease episode have a biopsy proven indolent recurrence, may be included. Subjects with proven or suspected Richter transformation are not eligible.
5. Have Waldenstrom’s Macroglobulinemia or FL3B, due to the high risk of transformation while on study.
6. Need systemic doses of prednisolone >10 mg daily (or equipotent doses of other corticosteroids) while on the study other than as pre-medication. During the screening period, doses of up to 20 mg/day may be given but the dose must be reduced to 10 mg/day within 7 days prior the first dose of study drug. Inhaled or intranasal steroids are permissible.
7. Have known or suspected hypersensitivity to rituximab or BI-1206. Previous isolated IRRs are not to be considered a reason for exclusion.
8. Have cardiac or renal amyloid light-chain amyloidosis.
9. Have received any of the following:
• Chemotherapy or small molecule products with 2 weeks of first dose of BI- 1206 and/or
• Radiotherapy (except for focal symptomatic control of lymphadenopathy) within 4 weeks of first dose of BI-1206 and/or
• Immunotherapy within 8 weeks prior to the first dose of BI-1206. Subjects receiving BI-1206 with rituximab and acalabrutinib: previous lines of treatment containing BTK inhibitors.
10. Have ongoing toxic manifestations of previous treatments. Exceptions to this are alopecia or certain Grade 1 toxicities, which in the opinion of the Investigator should not exclude the subject.
11.Have the ability to become pregnant (or already pregnant or lactating/breastfeeding). However, those female subjects who have a negative serum pregnancy test before enrollment and agree to use a highly effective method of birth control for 4 weeks before entering the trial, during the trial and for 12 months after last dose of BI 1206 are considered eligible. Highly effective methods of birth control include:
• Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation
• Progestogen-only hormonal contraception associated with inhibition of ovulation
• Intrauterine device
• Intrauterine hormone-releasing system
• Bilateral tubal occlusion
• Vasectomized partner
• Sexual abstinence
12. Are male subjects with partners of childbearing potential (unless they agree not to father children by using one form of highly effective contraception (condom plus spermicide gel) during the trial and for 12 months after completing treatment). Men with pregnant or lactating partners should be advised to use barrier method contraception (condom plus spermicidal gel) to prevent exposure to the fetus or neonate.
13. Have had major surgery from which the subject has not yet recovered.
14. Are at high medical risk because of non-malignant systemic disease including active infection on treatment with antibiotics, antifungals or antivirals.
15. Are serologically positive for hepatitis B, hepatitis C or human immunodeficiency virus (HIV).
16. Have an active, known or suspected autoimmune disease. However, subjects with Type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia not requiring systemic treatment), or conditions not expected to recur in the absence of an external trigger will be permitted to participate.
17. Have concurrent congestive heart failure, prior history of class III/ IV cardiac disease (New York Heart Association [NYHA]), history of clinically significant cardiac ischemia or cardiac arrhythmia in the past 6 months.
18. Have ongoing alcohol or drug addiction, as judged by the Investigator.
19. Have any other condition which in the Investigator’s opinion would not make the subject a good candidate for the clinical trial.
20. Are participating or plan to participate in another interventional clinical study, while taking part in this Phase 1/2a study of BI-1206. Participation in an observational non-interventional study is acceptable.
21. Have current malignancies of other types, with the exception of:
• adequately treated cone-biopsied in situ carcinoma of the cervix uteri
• basal or squamous cell carcinoma of the skin
• asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate-specific antigen for >1 year prior to start of study therapy.
Cancer survivors, who have undergone potentially curative therapy, have no evidence of that disease for ≥ 3 years and are deemed at negligible risk for recurrence, are also eligible for the trial. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Documenting AEs and SAEs (graded according to National Cancer
Institute [NCI] Common Terminology Criteria for Adverse Events CTCAE, and determining causality in relation to BI 1206, rituximab or acalabrutinib. Causality of AEs/SAEs will be assessed by the Investigator.
Phase 1
• Determining the MTD of BI-1206, with no more than 1 of up to 6 subjects at the same dose level experiencing DLT during the 28-day treatment period on induction therapy (i.e., by Day 29/Week 5). If pharmacokinetic (PK) and pharmacodynamic (PD) data suggest an optimal therapeutic dose, the escalation may be halted by the Cohort Review Committee (CRC) prior to reaching the MTD, and the RP2D will be based off the PK, PD, safety tolerability and efficacy data.
Phase 2a, BI-1206 in Combination with Rituximab and Acalabrutinib: The recommended dose will be derived from tot lity of PK, PD, clinical
response, safety, and tolerability observed. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At prespecified time points throughout the trial. |
|
| E.5.2 | Secondary end point(s) |
• Evaluation of PK parameters for BI-1206 during the BI-1206 treatment period.
• Evaluation of ADA response to BI 1206.
• Measurement of B cell depletion.
• Assessment of overall response rate (ORR) according to the response criteria for malignant lymphoma (Cheson, 2014). Other endpoints will include time to objective response, duration of response, PFS, and OS.
• CD32b protein expression levels.
• Expression levels of CD32b and/or other immunological markers. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At prespecified time points throughout the trial. |
|
| 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 | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| 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 |
|
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Dose escalation, consecutive-cohort |
|
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 11 |
| 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 |
| Brazil |
| United States |
| Germany |
| Spain |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 13 |
| 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 | 13 |
| 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 |
Print
