Copanlisib and Rituximab in Marginal Zone Lymphoma Patients - A MULTICENTER OPEN LABEL SINGLE-ARM PHASE II STUDY (COUP-1)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

University Hospital Of 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

4 Nov 2019 → ongoing

Decision date (initial)

2024-09-12

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Bayer AG; Celltrion Inc.

External identifiers

EU CT number

2022-500674-34-00

EudraCT number

2017-003150-16

ClinicalTrials.gov

NCT03474744

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety

The objective of the trial is to test the efficacy and toxicity of treatment with Copanlisib and Rituximab in patients with MZL in need of treatment, who have failed or are not eligible for local therapy or relapsed. For efficacy the rate of complete remissions (according to the GELA criteria for gastric MALT or to the Cheson 2007 criteria for non-gastric extranodal, nodal and splenic MZL) at 12 month 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

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 23

1. Confirmed CD20 positive MALT Lymphoma de novo or relapsed 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
2. Confirmed CD20 positive de novo or relapsed splenic MZL following or not being eligible for local therapy (including surgery and antiviral therapy for Hepatitis C Virus) with symptomatic disease: 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 (acceptable up to 12 weeks before start of treatment) must be submitted for retrospective central confirmation. OR
3. Confirmed CD20 positive de novo or relapsed nodal MZL
4. Tissue diagnostic procedures must be performed within 12 months prior to study entry and have to include diagnostics by a reference pathology center.
5. 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.
6. For nodal MZL and EMZL: At least one bi-dimensionally measurable lesion (≥ 1.5 cm in its largest dimension by CT scan or MRI)
7. For SMZL: For splenic MZL, an enlarged spleen on CT scan and lymphoma cell infiltration has to be seen in bone marrow and/or peripheral blood. At least one of the following criteria 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) – SMZL with concomitant hepatitis C infection which has not responded to or has relapsed after Interferon and/or Ribavirin and/or direct antiviral agents (patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA). – splenectomised patients with rapidly raising lymphocyte counts, development of lymphadenopathy or involvement of extranodal sites if not being eligible for local therapy.
8. For gastric MALT lymphoma, the clinical evidence of the MZL as seen by gastroendoscopy is sufficient. There is no need to show a measurable lesion by CT scan or MRI. Inclusion is possible for patients with: a) H. pylori-negative disease de novo or following or being not eligible for local therapy (i.e., surgery, radiotherapy or antibiotics) or after systemic therapy. b) H. pylori–positive disease that has remained stable, progressed, or relapsed following antibiotic therapy.
9. Age >=18 years
10. Life expectancy >3 months
11. Baseline platelet count >=50 G/L (if not due to BM infiltration by the lymphoma), absolute neutrophil count >=0.75 G/L
12. ASAT (SGOT): <=3 times the upper limit of institutional laboratory normal value
13. ALAT (SGPT): <=3 times the upper limit of institutional laboratory normal value
14. Total Bilirubin: <=2 mg/dL or 2 times the upper limit of institutional laboratory normal value, unless clearly related to the disease (except if due to Gilbert’s syndrome)
15. GFR ≥ 40 mL/min/1.73 m²
16. Negative HIV antibody
17. Positive test results for chronic HBV infection (defined as positive HBsAg serology): 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.
18. Positive test results for hepatitis C (hepatitis C virus [HCV] antibody serology testing): patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA.
19. Pregnancy β-HCG negative. For women of child-bearing potential only (i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy); serum or urine β-HCG must be negative during screening and at study enrolment visit
20. Premenopausal fertile females must agree to use a highly effective method of birth control for the duration of the therapy up to 12 months after end of therapy.
21. Men must agree not to father a child for the duration of therapy and 6 months after (use of a condom) and must agree to advice a female partner to use a highly effective method of birth control.
22. Willingness and ability to comply with scheduled visits, drug administration plan, imaging studies, laboratory tests, other study procedures, and study restrictions.
23. 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 21

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 enrolment visit
6. Ongoing drug-induced liver injury, chronic active hepatitis B (HBV), alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cholangitis, extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, or portal hypertension.
7. Ongoing alcohol or drug addiction
8. 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
9. Breastfeeding or pregnancy
10. Prior treatment with Copanlisib
11. Congestive heart failure > New York Heart Association (NYHA) class 2
12. Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months).
13. Myocardial infarction less than 6 months before start of test drug
14. Uncontrolled arterial hypertension despite optimal medical management
15. HbA1c>8.5%
16. 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.
17. History of anaphylaxis in association with previous administration of monoclonal antibodies.
18. Vaccination with a live vaccine within 28 days prior to start of therapy
19. Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 3 months before the start of study medication
20. Non-healing wound, ulcer, or bone fracture
21. History or concurrent interstitial lung disease of any severity and/or severely impaired lung function (as judged by the investigator).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Primary endpoint is the complete response (CR rate (CRR) determined 12 months after start of induction therapy, i.e. month 6 of maintenance). Patients who progress before 12 months after start of treatment 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.

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 and 12 months after start of 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. Duration of Response (DR): Duration of response as defined as the period from the first response (at least PR) to treatment until evidence of disease progression, relapse or death of 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 FACT-Lym (see Appendix H) before start of treatment, during induction and maintenance.

Investigational products

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

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

University Hospital Of Ulm AöR

Sponsor organisation

University Hospital Of Ulm AöR

Address

Albert-Einstein-Allee 29, Eselsberg Eselsberg

City

Ulm

Postcode

89081

Country

Germany

Scientific contact point

Organisation

University Hospital Of Ulm AöR

Contact name

Prof. Dr Christian Buske

Public contact point

Organisation

University Hospital Of Ulm AöR

Contact name

Prof. Dr Christian Buske

Locations

1 EU/EEA country · 13 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 6 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