Copanlisib in Combination With Venetoclax in Patients With Relapsed or Refractory B-cell Non-Hodgkin Lymphoma.

NCT03886649 | Terminated Phase 1 DMC

• 1 other identifier: SAKK 66/18
• Study Type: interventional
• Target: 7
• Locations: 1 country
• Sites: 6

Brief Summary

A significant number of patients with non-Hodgkin lymphoma (NHL) are not cured with available treatments and will eventually relapse. Those patients might not be able to tolerate more bone marrow toxicity, limiting their treatment options. Preclinical in vitro studies have demonstrated a synergism of venetoclax and copanlisib in different lymphomas. This may represent a safe and effective therapy for patients who relapsed or did not respond to standard therapy. The primary objective of this phase I trial is to establish the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of copanlisib in combination with venetoclax in patients with relapsed or refractory B-cell NHL.

Conditions

Non-Hodgkin Lymphoma

Keywords

Relapsed or refractory B-cell non-Hodgkin lymphoma; Copanlisib; Venetoclax; Non-Hodgkin lymphoma; Splenic marginal zone lymphoma; Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma); Nodal marginal zone lymphoma; Follicular lymphoma; Diffuse large B-cell lymphoma (DLBCL), NOS

Outcome Measures

Primary Outcomes (1)

• Dose-limiting toxicities (DLTs) during the first cycle of treatment

  Dose-limiting toxicity (DLT) is defined as any of the adverse events (AEs) which: * occurs during cycle 1 of the trial treatment (defined as the DLT monitoring period), and * is considered by the investigator or the sponsor to be at least possibly related to at least one of the drugs given in the combination trial treatment venetoclax+copanlisib.

  day 28 of the first cycle

Secondary Outcomes (5)

• Adverse events (AEs)

  at 12 months

• Complete response (CR) at 6 months and 12 months

  at 6 months and 12 months

• Overall response (OR) at 6 months and 12 months

  at 6 months and 12 months

• OR based on best response

  at 12 months

• Progression-free survival (PFS) at 12 months

  at 12 months

Study Arms (1)

Copanlisib + Venetoclax

EXPERIMENTAL

Phase Ib -\> dose escalation with 2 expansion cohorts

Drug: Copanlisib; Drug: Venetoclax

Interventions

Copanlisib DRUG

Duration of IMP administration: a maximum of twelve 28-day cycles of the combination treatment. Copanlisib will be administered i.v. on days 1, 8, and 15 of each cycle. The only dose level 1 (DL1) is 60 mg copanlisib.

Copanlisib + Venetoclax

Venetoclax DRUG

Duration of IMP administration: a maximum of twelve 28-day cycles of the combination treatment. Copanlisib will be administered i.v. on days 1, 8, and 15 of each cycle. The starting dose is dose level 1 (DL1): 600 mg venetoclax.

Copanlisib + Venetoclax

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent according to Swiss law and ICH/GCP regulations before registration and prior to any trial specific procedures.
• Histologically confirmed B-cell NHL lymphoma as per WHO classification for the escalation phase. FL or MZL for the expansion phase.
• Patients with relapsed or refractory disease who have failed previous treatment (including chemotherapy plus anti CD20) for whom no effective standard treatment is available or refused by the patient.
• Patients with a prior malignancy and treated with curative intention are eligible if all treatment of that malignancy was completed at least 2 years before registration and the patient has no evidence of disease at registration. Less than 2 years is acceptable for malignancies with low risk of recurrence and/or no late recurrence.
• \> 1 two-dimensionally measurable nodal lesion in CT, PET/CT scan (preferable) or MRI, according to Cheson et al, 2014.
• Tumor tissue (formalin fixed paraffin embedded (FFPE) slides/rolls) is available for the mandatory translational research.
• Age ≥ 18 years.
• WHO performance status 0-1
• Adequate bone marrow function:
• Absolute neutrophil count (ANC) \>1.5 × 109/l (1 × 109/l if due to bone marrow involvement by lymphoma). Patient must not have received any hematologic growth factor within 14 days prior to registration.
• Platelet count \>100 ×109/l (75 ×109/l if due to bone marrow involvement by lymphoma)
• Adequate hepatic function:
• total bilirubin ≤ 1.5 × ULN (except for patients with Gilbert's disease ≤ 3.0 × ULN),
• AST and ALT ≤ 2.5 × ULN, or ≤ 5 × ULN under the assumption that abnormal values are tumor related.
• Adequate renal function: estimated glomerular filtration rate (eGFR) ≥ 50 ml/min/1.73 m2 (according to CKD-EPI formula)

You may not qualify if:

• Patients with CLL/SLL.
• Patients that require ramp-up of venetoclax, including MCL. Other histologies will be discussed with the coordinating investigator (CI).
• Presence or history of CNS disease (either CNS lymphoma or lymphomatous meningeosis). Primary CNS disease.
• Prior treatment with venetoclax, copanlisib or any other bcl-2 inhibitors or PIK3 inhibitors.
• Prior allogeneic stem cell transplant (SCT), or autologous transplant less than 3 months prior to registration.
• Concomitant or recent treatment with any other experimental drug (enrollment in another clinical trial.
• Treatment with any anti-lymphoma therapies within 21 days prior to registration - except for local radiation therapy for palliative treatment of symptoms.
• Not resolved grade ≥ 2 (per NCI CTCAE v5.0 toxicity (other than alopecia) from prior therapy at registration.
• Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV; (see Appendix 4), unstable or new onset angina pectoris, history of myocardial infarction within the last six months, serious arrhythmias requiring medication (with exception of atrial fibrillation or paroxysmal supraventricular tachycardia), significant QT-prolongation.
• Uncontrolled hypertension (sustained systolic blood pressure \>150 mmHg and or diastolic \>90 mmHg) despite optimal medical management (per investigator's assessment).
• Proteinuria of ≥ CTCAE grade 3 as assessed by a 24h total urine protein quantification or on a random urine sample, estimated by urine protein to creatinine ratio \> 3.5.
• HbA1c \> 8.5%.
• Lipase ≥ 1.5 x ULN.
• History of cerebrovascular accident or intracranial hemorrhage within 6 months prior to registration.
• Major surgery within 1 month prior to registration.

Sponsors & Collaborators

• Swiss Cancer Institute: lead

Study Sites (6)

Universitaetsspital Basel

Basel, 4031, Switzerland

Location

Istituto Oncologico della Svizzera Italiana

Bellinzona, 6500, Switzerland

Location

Inselspital

Bern, 3010, Switzerland

Location

Hôpitaux Universitaires de Genève

Geneva, 1211, Switzerland

Location

Kantonsspital St. Gallen

Sankt Gallen, 9007, Switzerland

Location

UniversitätsSpital Zürich

Zurich, 8091, Switzerland

Location

MeSH Terms

Conditions

Lymphoma, Non-Hodgkin; Recurrence; Lymphoma, B-Cell; Lymphoma, B-Cell, Marginal Zone; Lymphoma, Follicular; Dendritic Cell Sarcoma, Interdigitating

Interventions

copanlisib; venetoclax

Condition Hierarchy (Ancestors)

Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Histiocytic Disorders, Malignant; Histiocytosis

Study Officials

• Anastasios Stathis, MD

  IOSI, Ospedale San Giovanni, Bellinzona

  STUDY CHAIR

• Emanuele Zucca

  IOSI, Ospedale San Giovanni, Bellinzona

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: In the dose escalation phase, relapsed/refractory B-cell NHL patients are included. In the dose expansion phase, patients with MZL (Marginal zone lymphoma) and FL (Follicular lymphoma) will be treated.

Study Record Dates

• First Submitted: March 21, 2019
• First Posted: March 22, 2019
• Study Start: November 4, 2019
• Primary Completion: May 10, 2021
• Study Completion: March 8, 2022
• Last Updated: April 1, 2022

Record last verified: 2022-03

Locations

CH (6)