Obinutuzumab in marginal zone lymphoma - A MULTICENTER OPEN LABEL SINGLE-ARM PHASE II STUDY (OLYMP-1)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitaetsklinikum Ulm AöR

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

14 May 2018 → ongoing

Decision date (initial)

2024-09-05

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

ROCHE Pharma AG

External identifiers

EU CT number

2024-517476-38-00

EudraCT number

2017-003149-56

ClinicalTrials.gov

NCT03322865

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Safety

The objective of the trial is to test the efficacy and toxicity of first line treatment with single agent Obinutuzumab in patients with MZL in need of treatment, who have failed or are not eligible for local therapy. For efficacy the rate of complete remissions (according to the GELA criteria for gastric MALT or to the Cheson 2007 criteria for nodal and splenic MZL) after induction therapy will be primarily analysed. For toxicity treatment associated adverse events, quality of life and cumulative incidence of secondary malignancies will be documented.

Conditions and MedDRA coding

Marginal Zone Lymphoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 16

1. Confirmed CD20 positive de novo MALT Lymphoma following or being not eligible for local therapy (including surgery, radiotherapy) and antibiotics for H. pylori-positive gastric lymphoma arisen at any extranodal site OR Confirmed CD20 positive de novo splenic MZL following or not being eligible for local therapy (including surgery and antiviral therapy for Hepatitis C Virus) with symptomatic disease OR Confirmed CD20 positive de novo nodal MZL Tissue diagnostic procedures must be performed within 12 months prior to study entry and have to include diagnostics by a reference pathology center. Biopsy material from an excisional or core biopsy must be submitted for retrospective central confirmation. Tissue samples dated > 12 months prior to informed consent can be accepted only if tissue material is available for retrospective confirmation, if there is no clinical indication for transformation of disease, and if the request for additional biopsy would be unethical treatment of the patient. In patients with splenic MZL without splenic tissue available for histologic review, the diagnosis may be confirmed by the presence of splenomegaly and typical morphologic and immunophenotypic findings in the blood and bone marrow. Bone marrow must be submitted for retrospective central confirmation.
2. Patients in need of treatment: For patients with symptomatic splenic, nodal, or non-gastric extranodal MZL disease that is de novo or has relapsed following local therapy (i.e., surgery or radiotherapy) and requires therapy, as assessed by the investigator. For patients with symptomatic gastric extranodal MZL: Helicobacter pylori-negative disease that is de novo or has relapsed following local therapy (i.e., surgery or radiotherapy) and requires therapy, as assessed by the investigator, or H. pylori–positive disease that has remained stable, progressed, or relapsed following antibiotic therapy and requires therapy, as assessed by the investigator
3. At least one bi-dimensionally measurable lesion (≥ 1.5 cm in its largest dimension by CT scan or MRI). For an enlarged liver to constitute the only measurable disease parameter, a liver biopsy showing proof of NHL in the liver is required.
4. For SMZL: In patients with splenic MZL, an enlarged spleen on CT scan or extending at least 2 cm below the costal margin by physical examination will constitute measurable disease providing that no explanation other than lymphomatous involvement is likely. At least one of the following must be met: – Bulky progressive or painful splenomegaly – one of the following symptomatic/progressive cytopenias: Hb < 10 g/dL, or Plat < 80.000 /μL, or neutropenia < 1000/μL, whatever the reason (autoimmune or hypersplenism or bone marrow infiltration) – enlarged lymphoadenopathy or involvement of extranodal sites with or without cytopenia – splenectomised patients with rapidly raising lymphocyte counts, development of lymphadenopathy or involvement of extranodal sites – SMZL with concomitant hepatitis C infection who have not responded to or are relapsed after Interferon and/or Ribavirin (patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA).
5. For gastric MALT Lymphoma: – H. pylori-negative disease de novo or following or being not eligible for local therapy (i.e., surgery, radiotherapy or antibiotics). – H. pylori–positive disease that has remained stable, progressed, or relapsed following antibiotic therapy.
6. Age ≥ 18 years
7. Life expectancy >3 months.
8. Baseline platelet count ≥ 50 x10^9/L (if not due to BM infiltration by the lymphoma), absolute neutrophil count ≥ 0.75x10^9/L.
9. Meet the following pretreatment laboratory criteria at the Screening visit conducted within 28 days of study enrollment (unless due to underlying lymphoma): – ASAT (SGOT): ≤3 times the upper limit of institutional laboratory normal value – ALAT (SGPT): ≤3 times the upper limit of institutional laboratory normal value – Total Bilirubin: ≤20 mg/L or 2 times the upper limit of institutional laboratory normal value, unless clearly related to the disease (except if due to Gilbert’s syndrome)
10. Serum creatinine ≤ 2mg/dl
11. Negative HIV antibody
12. Pregnancy β-HCG negative. For women of child-bearing potential only; serum or urine β-HCG must be negative during screening and at study enrolment visit (Day 1 of Cycle 1, defined as the day of the first dose of OBINUTUZUMAB)
13. Premenopausal fertile females must agree to use a highly effective method of birth control for the duration of the therapy up to 18 months after end of therapy. A highly effective method of birth control is defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, some IUDs, sexual abstinence or vasectomised partner. Post-menopausal (a practical definition accepts menopause ≥ 1 year without menses with an appropriate clinical profile, e.g. age >45 years in the absence of hormone replacement therapy (HRT). In questionable cases, the subject must have a follicle stimulating hormone (FSH) value >40 mIU/mL and an estradiol value < 40pg/mL).
14. Men must agree not to father a child for the duration of therapy and 6 months after and must agree to advice a female partner to use a highly effective method of birth control.
15. Willingness and ability to comply with scheduled visits, drug administration plan, imaging studies, laboratory tests, other study procedures, and study restrictions.
16. Evidence of a personally signed informed consent indicating that the subject is aware of the neoplastic nature of the disease and has been informed of the procedures to be followed, the experimental nature of the therapy, alternatives, potential benefits, possible side effects, potential risks and discomforts, and other pertinent aspects of study participation.

Exclusion criteria 14

1. ECOG performance status >2
2. History of a non-lymphoid malignancy except for the following: adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, 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 study enrollment visit, other Stage 1 or 2 cancer treated with a curative intent and currently in complete remission, for ≥3 years.
3. Central nervous system lymphoma, leptomeningeal lymphoma, or histologic evidence of transformation to a high-grade or diffuse large B-cell lymphoma.
4. Ongoing immunosuppressive therapy including corticosteroids (exception < 4 weeks administered at a dose equivalent to ≤ 40 mg/day prednisone is allowed)
5. Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of study enrollment visit
6. Ongoing drug-induced liver injury, chronic active hepatitis B (HBV), alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, or portal hypertension.
7. Ongoing alcohol or drug addiction
8. Breastfeeding or pregnancy
9. Prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, electrocardiogram (ECG) finding, or laboratory abnormality that, in the investigator’s opinion, could adversely affect the safety of the subject or impair the assessment of study results.
10. Patients positive for HBV infection. Patients with occult or prior HBV infection (defined as negative HBsAg and positive total HBcAb) may be included if HBV DNA is undetectable, provided that they are willing to undergo monthly DNA testing. Patients who have protective titers of HBSAb after vaccination or prior but cured hepatitis B are eligible. •
11. Patients positive for HCV infection. Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA.
12. History of anaphylaxis in association with previous administration of monoclonal antibodies.
13. Vaccination with a live vaccine within 28 days prior to start of therapy
14. Treatment with any other investigational agent within 30 days or within 5 x the half life (t1/2) of the investigational product, whichever is longer, or participating in another trial within 30 days prior to entering this study

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Primary endpoint is the complete response (CR rate (CRR) determined after induction therapy). Patients who progress before EOI will be treated as CR=’NO’ and will be included in the calculation of the primary endpoint. No primary endpoint will be determined for patients who withdraw. These patients will be excluded from the confirmatory data analysis but will be analyzed in a separate exploratory sensitivity analysis of the primary endpoint.

Secondary endpoints 10

1. Response rate: The response rates (complete response (CR), partial response (PR)) and overall response rate (CR or PR) are evaluated 4 weeks after the end of induction treatment.
2. Best response: Best response is determined in the time interval from the start of induction therapy to end of follow-up.
3. Time to best response: Time to best response is defined as the time from the start of induction to best response the patient achieves (CR, PR).
4. Time to first response: Time to first response is defined as the time from the start of induction to first response (CR, PR).
5. Progression free survival (PFS): Progression free survival (PFS) is defined as the time from registration to the first occurrence of progression or relapse as assessed by the investigator, or death from any cause. PFS for patients without disease progression, relapse, or death will be censored at the time of the last tumor assessment.
6. Time to treatment failure (TTF): Time to treatment failure (TTF) is defined as the time of registration to discontinuation of therapy for any reason including death from any cause, progression, toxicity or add-on of new anti-cancer therapy. Patients alive without treatment failure are censored at the latest tumor assessment date.
7. Remission duration (RD): Remission duration will be calculated in patients with response (CR, PR) to induction from end of induction to the date of progression, relapse or death from any cause. Patients alive without progression and relapse will be censored at the latest tumor assessment date or the stopping date.
8. Cause specific survival (CSS): Cause specific survival is defined as the period from the induction registration to death from lymphoma or lymphoma related cause; death unrelated to MZL is considered as a competing event.
9. Overall survival (OS): Overall survival is defined as the period from the induction registration to death from any cause. Patients who have not died until the time of the analysis will be censored at their last contact date.
10. Quality of life during induction and maintenance therapy: Quality of life will be measured by the FACTLym (see Appendix G) before start of treatment, during induction and maintenance.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitaetsklinikum Ulm AöR

Sponsor organisation

Universitaetsklinikum Ulm AöR

Address

Albert-Einstein-Allee 29, Eselsberg Eselsberg

City

Ulm

Postcode

89081

Country

Germany

Scientific contact point

Organisation

Universitaetsklinikum Ulm AöR

Contact name

Prof. Dr. Christian Buske

Public contact point

Organisation

Universitaetsklinikum Ulm AöR

Contact name

Prof. Dr. Christian Buske

Third parties 4

Locations

1 EU/EEA country · 12 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 4 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications