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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03886649
Recruitment Status : Recruiting
First Posted : March 22, 2019
Last Update Posted : October 9, 2019
Information provided by (Responsible Party):
Swiss Group for Clinical Cancer Research

Tracking Information
First Submitted Date  ICMJE March 21, 2019
First Posted Date  ICMJE March 22, 2019
Last Update Posted Date October 9, 2019
Estimated Study Start Date  ICMJE October 2019
Estimated Primary Completion Date December 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 21, 2019)
Dose-limiting toxicities (DLTs) during the first cycle of treatment [ Time Frame: day 28 of the first cycle ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03886649 on Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 21, 2019)
  • Adverse events (AEs) [ Time Frame: at 12 months ]
  • Complete response (CR) at 6 months and 12 months [ Time Frame: at 6 months and 12 months ]
  • Overall response (OR) at 6 months and 12 months [ Time Frame: at 6 months and 12 months ]
  • OR based on best response [ Time Frame: at 12 months ]
  • Progression-free survival (PFS) at 12 months [ Time Frame: at 12 months ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Copanlisib in Combination With Venetoclax in Patients With Relapsed or Refractory B-cell Non-Hodgkin Lymphoma.
Official Title  ICMJE Copanlisib in Combination With Venetoclax in Patients With Relapsed or Refractory B-cell Non-Hodgkin Lymphoma. A Multicenter Phase Ib Trial With Two Expansion Cohorts
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.

Detailed Description

There are many different types of NHL. A lot of progress has been made over the last years in the management of NHL, and while some can be cured with available treatments, for others new treatments are necessary. A significant number of patients that cannot be cured with the available treatments will eventually relapse.

Dysregulation of apoptosis via overexpression of the antiapoptotic BCL-2 protein is paramount for several subtypes of NHL. On the other hand, PI3K is a central pathway in the pathogenesis of lymphoma, and PI3K signaling is critical for the proliferation and survival of malignant cells such as follicular lymphoma (FL), marginal zone lymphoma (MZL), and others.

The combination of copanlisib (PI3K inhibitor) and venetoclax (BLC-2 inhibitor) is interesting given their known single agent activity in B-cell NHL and their synergy observed in B-cell NHL preclinical models. The pharmacologic inhibition of PI3K by copanlisib has translated into significant clinical activity in different lymphoma subtypes. Venetoclax has proven successful in CLL and the first results in NHL are encouraging. Both compounds are currently in other combination studies in SLL/CLL and NHL but there are currently no clinical trials studying this particular combination.

There is a need to further improve approaches in the relapsed/refractory setting of patients with NHL in need of systemic therapy and this combination may provide an opportunity for an active and well-tolerated regimen that does not present the short and long-term toxicities of chemotherapy.

The phase Ib study here proposed will evaluate the safety, tolerability and preliminary antitumor activity of the novel combination of copanlisib with venetoclax, two drugs with single agent activity across different lymphoma subtypes in the dose escalation and in two small cohorts of patients with FL and MZL in the expansion phase.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Intervention Model Description:
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.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Non-Hodgkin Lymphoma
Intervention  ICMJE
  • Drug: Copanlisib
    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.
  • Drug: Venetoclax
    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.
Study Arms  ICMJE Experimental: Copanlisib + Venetoclax
Phase Ib -> dose escalation with 2 expansion cohorts
  • Drug: Copanlisib
  • Drug: Venetoclax
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 21, 2019)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2022
Estimated Primary Completion Date December 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • 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:

    1. 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.
    2. Platelet count >100 ×109/l (75 ×109/l if due to bone marrow involvement by lymphoma)
  • Adequate hepatic function:

    1. total bilirubin ≤ 1.5 × ULN (except for patients with Gilbert's disease ≤ 3.0 × ULN),
    2. 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)
  • Adequate cardiac function: Left ventricular Ejection Fraction (LVEF) ≥ 50% as determined by echocardiography (ECHO).
  • Adequate coagulation function: INR ≤ 1.5 × ULN (the ULN for INR is defined with the value 1.2 for all sites, in case no ULN is documented in the lab certificates/sheets), aPTT ≤ 1.5 × ULN.
  • Women of childbearing potential (not surgically sterile or exceeding 2 years after the onset of menopause) must use highly effective contraception, are not pregnant or lactating and agree not to become pregnant during trial treatment and until 3 months after the last dose of investigational drug. A negative pregnancy test before inclusion into the trial is required for all women of childbearing potential.
  • Men agree not to donate sperm or to father a child during trial treatment and until 3 months after the last dose of investigational drug.
  • Patient is able and willing to swallow trial drug as whole tablet.

Exclusion Criteria:

  • 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.
  • Known history of human immunodeficiency virus (HIV) or active chronic Hepatitis C or Hepatitis B Virus infection or any uncontrolled active systemic infection requiring intravenous (iv) antimicrobial treatment. All patients must be screened for HIV up to 28 days prior to study drug start using a blood test for HIV according to local regulations. All patients must be screened for hepatitis up to 28 days prior to study drug start using the routine hepatitis virus laboratory panel. Patients positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) will be eligible if they are negative for HBV-DNA, these patients should receive prophylactic antiviral therapy. Patients positive for anti-HCV antibody will be eligible if they are negative for HCV-RNA.
  • Active CMV infection. Patients who are CMV PCR positive at baseline will be excluded.
  • Malabsorption syndrome or other condition that precludes enteral route of administration.
  • Concomitant or prior use of immunosuppressive medication within 28 days before registration, with the exceptions of intranasal and inhaled corticosteroids, or systemic corticosteroids which must not exceed 10 mg/day of prednisone or a dose equivalent corticosteroid).
  • Has active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  • Concomitant anticoagulation treatment with warfarin or equivalent vitamin K antagonists (e.g. phenprocoumon), factor Xa inhibitors (e.g. rivaroxaban, apixaban), direct thrombin inhibitors (e.g. dabigatran) or platelet inhibitors/antiplatelet agents. Exception: Aspirin (up to 300 mg/day) is allowed.
  • Concomitant treatment with strong CYP3A inducers or inhibitors (see and the FDA database of drug interactions. Concomitant treatment with moderate inhibitors or inducers during the DLT period.
  • Any concomitant drugs contraindicated for use with the trial drugs according to the approved product information.
  • Known hypersensitivity to trial drug(s) or to any component of the trial drug(s).
  • Any other serious underlying medical, psychiatric, psychological, familial or geographical condition, which in the judgment of the investigator may interfere with the planned staging, treatment and follow-up, affect patient compliance or place the patient at high risk from treatment-related complications.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Lena Sokol, PhD +41 31 389 91 91
Listed Location Countries  ICMJE Switzerland
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT03886649
Other Study ID Numbers  ICMJE SAKK 66/18
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Swiss Group for Clinical Cancer Research
Study Sponsor  ICMJE Swiss Group for Clinical Cancer Research
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Anastasios Stathis, MD IOSI, Ospedale San Giovanni, Bellinzona
Study Chair: Emanuele Zucca IOSI, Ospedale San Giovanni, Bellinzona
PRS Account Swiss Group for Clinical Cancer Research
Verification Date October 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP