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

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ClinicalTrials.gov Identifier: NCT03886649
Recruitment Status : Recruiting
First Posted : March 22, 2019
Last Update Posted : September 17, 2019
Sponsor:
Information provided by (Responsible Party):
Swiss Group for Clinical Cancer Research

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.


Condition or disease Intervention/treatment Phase
Non-Hodgkin Lymphoma Drug: Copanlisib Drug: Venetoclax Phase 1

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 38 participants
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
Official Title: 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
Estimated Study Start Date : October 2019
Estimated Primary Completion Date : December 2022
Estimated Study Completion Date : December 2022


Arm Intervention/treatment
Experimental: Copanlisib + Venetoclax
Phase Ib -> dose escalation with 2 expansion cohorts
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.




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. Adverse events (AEs) [ Time Frame: at 12 months ]
  2. Complete response (CR) at 6 months and 12 months [ Time Frame: at 6 months and 12 months ]
  3. Overall response (OR) at 6 months and 12 months [ Time Frame: at 6 months and 12 months ]
  4. OR based on best response [ Time Frame: at 12 months ]
  5. Progression-free survival (PFS) at 12 months [ Time Frame: at 12 months ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 http://medicine.iupui.edu/ 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03886649


Contacts
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Contact: Lena Sokol, PhD +41 31 389 91 91 trials@sakk.ch

Locations
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Switzerland
Universitaetsspital Basel Recruiting
Basel, Switzerland, 4031
Contact: Fatime Krasniqi, MD    +41 61 265 5059    KrasniqiF@uhbs.ch   
Principal Investigator: Fatime Krasniqi, MD         
Istituto Oncologico della Svizzera Italiana Recruiting
Bellinzona, Switzerland, 6500
Contact: Anastasios Stathis, MD    +41 91 811 89 31    anastasios.stathis@eoc.ch   
Principal Investigator: Anastasios Stathis, MD         
Inselspital, Bern Not yet recruiting
Bern, Switzerland, CH-3010
Contact: Urban Novak, MD    +41 31 632 19 92    urban.novak@insel.ch   
Principal Investigator: Urban Novak, MD         
Hôpitaux Universitaires de Genève Recruiting
Genève, Switzerland, 1211
Contact: Alex Friedlaender, MD    +41 22 372 29 01    alex.friedlaender@hcuge.ch   
Principal Investigator: Alex Friedlaender, MD         
Kantonsspital St. Gallen Recruiting
St. Gallen, Switzerland, 9007
Contact: Dagmar Hess, MD    +41 71 494 11 11    dagmar.hess@kssg.ch   
Principal Investigator: Dagmar Hess, MD         
UniversitätsSpital Zürich Recruiting
Zürich, Switzerland, 8091
Contact: Thorsten Zenz, Prof    +41 44 255 94 96    thorsten.zenz@usz.ch   
Principal Investigator: Thorsten Zenz, Prof         
Sponsors and Collaborators
Swiss Group for Clinical Cancer Research
Investigators
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Study Chair: Anastasios Stathis, MD IOSI, Ospedale San Giovanni, Bellinzona
Study Chair: Emanuele Zucca IOSI, Ospedale San Giovanni, Bellinzona

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Responsible Party: Swiss Group for Clinical Cancer Research
ClinicalTrials.gov Identifier: NCT03886649     History of Changes
Other Study ID Numbers: SAKK 66/18
First Posted: March 22, 2019    Key Record Dates
Last Update Posted: September 17, 2019
Last Verified: September 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Swiss Group for Clinical Cancer Research:
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
Additional relevant MeSH terms:
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Venetoclax
Lymphoma
Lymphoma, Non-Hodgkin
Lymphoma, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Antineoplastic Agents