Clinical Trials /

Copanlisib in Combination With Romidepsin in Patients With Relapsed or Refractory Mature T-cell Lymphoma

NCT04233697

Description:

This is an open label, Phase IB dose-escalation study of the PI3K inhibitor copanlisib in combination with romidepsin in patients with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma (HL). The primary objective of the phase I study is to determine the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), and dose limiting toxicities (DLTs) of the combination of copanlisib and romidepsin in patients with R/R, NHL or HL.

Related Conditions:
  • Hodgkin Lymphoma
  • Non-Hodgkin Lymphoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Copanlisib in Combination With Romidepsin in Patients With Relapsed or Refractory Mature T-cell Lymphoma
  • Official Title: Phase 1B Study of the PI3K Inhibitor Copanlisib in Combination With Romidepsin in the Treatment of Patients With Relapsed or Refractory Mature T-cell Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: AAAR5207
  • NCT ID: NCT04233697

Conditions

  • T-Cell Lymphoma Relapsed & Refractory

Interventions

DrugSynonymsArms
CopanlisibAliqopa, 80-6946Copanlisib and Romidepsin
RomidepsinIstodaxCopanlisib and Romidepsin

Purpose

This is an open label, Phase IB dose-escalation study of the PI3K inhibitor copanlisib in combination with romidepsin in patients with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma (HL). The primary objective of the phase I study is to determine the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), and dose limiting toxicities (DLTs) of the combination of copanlisib and romidepsin in patients with R/R, NHL or HL.

Detailed Description

      The non-Hodgkin lymphomas (NHL) represent 4-5% of all new cancer cases, and is the seventh
      leading cause of cancer death. In 2015, there were an estimated 71,850 cases in the United
      States, and approximately 19,790 deaths. An evaluation of the distribution of NHL sub-types
      was performed on 114,548 cases of lymphoid neoplasms diagnosed between 1992-2001 and reported
      to the Surveillance Epidemiology and End Results (SEER) registry. Of all NHL, 87,666 were
      B-cell lymphoid neoplasms, and 6,228 were considered T/Natural Killer (NK) cell neoplasms.

      The peripheral T-cell lymphomas (PTCL) are a heterogeneous group of aggressive lymphoid
      neoplasms and account for 10-15% of all newly diagnosed cases of NHL. The current prevalence
      of PTCL in the United States is estimated to be approximately 9,500 patients. PTCL-Not
      Otherwise Specified (NOS), a nodal subtype, is the most common T-cell lymphoma in the United
      States and Europe. PTCL is associated with a significantly worse prognosis compared to its
      B-cell counterparts. Treatment options for patients with relapsed/refractory (R/R) PTCL have
      been limited. The addition of novel drugs to conventional chemotherapy has largely proven
      unsuccessful. Since 2009, new drugs have entered the therapeutic field for patients with R/R
      PTCL.

      Pralatrexate was the first drug approved for patients with R/R PTCL. Other drugs approved for
      patients with R/R PTCL include romidepsin and belinostat. These agents appear to exhibit
      lineage-specific activity in PTCL. Over the past few years, the investigators have focused on
      exploring rational combinations of these T-cell active agents in an effort to develop novel
      treatment platforms. Early clinical studies of these combinations have shown very promising
      activity.
    

Trial Arms

NameTypeDescriptionInterventions
Copanlisib and RomidepsinExperimentalCopanlisib and romidepsin will be both administered via IV (through a vein in arm) on days 1, 8, and 15 every 28 days, also called a "cycle".
  • Copanlisib
  • Romidepsin

Eligibility Criteria

        Inclusion Criteria:

          -  Be willing and able to provide written informed consent for the trial.

          -  Be ≥18 years of age on day of signing informed consent.

          -  Have measurable disease based on the Lugano Criteria.

          -  Phase I: patient must have histologically confirmed R/R NHL or HL (defined by World
             Health Organization (WHO) criteria).

          -  Expansion phase: patients must have histologically confirmed R/R mature T-cell
             lymphoma (defined by WHO criteria).

          -  Patient must have received at least two prior lines of therapy prior to enrollment in
             this study.

          -  Have a performance status of 0-2 on the Eastern Cooperative Oncology Group (ECOG)
             Performance Scale.

          -  Left Ventricular Ejection Fraction (LVEF) > 50%.

          -  Demonstrate adequate organ function. All screening labs should be performed within 10
             days of treatment initiation. The following treatments are prohibited: (a)
             Chemotherapy, monoclonal antibody within 4 weeks; (b) radiotherapy within 2 weeks
             prior to entering the study; (c) systemic steroids that have not been stabilized (≥ 5
             days) to the equivalent of ≤10 mg/day prednisone prior to the start of the study
             drugs; (d) other concurrent investigational agents within 4 weeks prior to entering
             the study; (e) use of copanlisib or romidepsin within the past 3 months.

          -  Patients that have not recovered from adverse events due to chemotherapy agents
             administered more than 4 weeks earlier.

          -  Hypersensitivity to copanlisib or romidepsin or any of its excipients.

          -  Patients that received major surgery and have not recovered adequately from the
             toxicity and/or complications from the intervention prior to starting therapy.

          -  Patients with active, clinically serious infections > CTCAE Grade 2.

          -  Patients with Cytomegalovirus (CMV) PCR positive at baseline.

          -  Patients with active infections including: active tuberculosis (TB), Hepatitis B
             (e.g., HBsAg reactive), Hepatitis C, Hepatitis A.

          -  Patients with uncontrolled inter-current illness (e.g. pneumonia).

          -  Patients with known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies

          -  Adequate Contraception.

        Exclusion Criteria:

          -  The following treatments are prohibited: (a) Chemotherapy, monoclonal antibody within
             4 weeks; (b) radiotherapy within 2 weeks prior to entering the study; (c) systemic
             steroids that have not been stabilized (≥ 5 days) to the equivalent of ≤10 mg/day
             prednisone prior to the start of the study drugs; (d) other concurrent investigational
             agents within 4 weeks prior to entering the study; (e) use of copanlisib or romidepsin
             within the past 3 months.

          -  Patients that have not recovered from adverse events due to chemotherapy agents
             administered more than 4 weeks earlier.

          -  Hypersensitivity to copanlisib or romidepsin or any of its excipients.

          -  Patients that received major surgery and have not recovered adequately from the
             toxicity and/or complications from the intervention prior to starting therapy.

          -  Patients with active, clinically serious infections > CTCAE Grade 2.

          -  Patients with CMV PCR positive at baseline.

          -  Patients with active infections including: active TB (Mycobacterium Tuberculosis),
             Hepatitis B (e.g., HBsAg reactive), Hepatitis C (e.g., HCV RNA [qualitative] is
             detected), Hepatitis A.

          -  Patients with uncontrolled inter-current illness (e.g. pneumonia).

          -  Patients with known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies
             The following treatments are prohibited: (a) Chemotherapy, monoclonal antibody within
             4 weeks; (b) radiotherapy within 2 weeks prior to entering the study; (c) systemic
             steroids that have not been stabilized (≥ 5 days) to the equivalent of ≤10 mg/day
             prednisone prior to the start of the study drugs; (d) other concurrent investigational
             agents within 4 weeks prior to entering the study; (e) use of copanlisib or romidepsin
             within the past 3 months.

          -  Patients that have not recovered from adverse events due to chemotherapy agents
             administered more than 4 weeks earlier.

          -  Hypersensitivity to copanlisib or romidepsin or any of its excipients.

          -  Patients that received major surgery and have not recovered adequately from the
             toxicity and/or complications from the intervention prior to starting therapy.

          -  Patients with active, clinically serious infections > CTCAE Grade 2.

          -  Patients with CMV PCR positive at baseline.

          -  Patients with active infections including: active TB (Mycobacterium Tuberculosis),
             Hepatitis B (e.g., HBsAg reactive), Hepatitis C (e.g., HCV RNA [qualitative] is
             detected), Hepatitis A.

          -  Patients with uncontrolled inter-current illness (e.g. pneumonia).

          -  Patients with known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies

          -  Patients with known active concurrent malignancy (except non-melanoma skin cancer,
             prostatic intraepithelial neoplasia, or carcinoma in situ of the cervix). If there is
             a history of prior malignancy, the patient must be disease-free for ≥ 3 years.

          -  Patients with known active central nervous system (CNS) metastases and/or
             carcinomatous meningitis and/or known lymphomatous involvement of the central nervous
             system.

          -  Evidence of active non-infectious pneumonitis (NIP).

          -  History of concurrent condition of interstitial lung disease of any severity and/or
             severely impaired lung function (as judged by the investigator).

          -  Patients with an active autoimmune disease that has required systemic treatment in the
             past 2 years (i.e. with use of disease modifying agents, corticosteroids or
             immunosuppressive drugs). Of note, replacement therapy (e.g. thyroxine, insulin, or
             physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency,
             etc.) is allowed for patient on study.

          -  Uncontrolled Type I or II diabetes mellitus as deemed appropriate by the investigator
             (suggested guidelines for uncontrolled diabetes: HbA1c> 8.5%).

          -  Uncontrolled hypertension, i.e., blood pressure (BP) of ≥ 150/90; patients who have a
             history of hypertension controlled by medication must be on a stable dose (for at
             least one month) and meet all other inclusion criteria.

          -  Concomitant use of CYP3A4 inhibitors.

          -  Congenital long QT syndrome and/or QTc interval ≥ 500 milliseconds.

          -  Patients taking drugs leading to significant QT prolongation.

          -  Any cardiac arrhythmia requiring an anti-arrhythmic medication, with the exception of
             stable doses of beta-blockers.

          -  Myocardial infarction within 6 months of cycle 1, day 1. [Subjects with a history of
             myocardial infarction between 6 and 12 months prior to cycle 1, day 1, who are
             asymptomatic and have had a negative cardiac risk assessment (treadmill stress test,
             nuclear medicine stress test, or stress echocardiogram) since the event, may
             participate].

          -  Symptomatic coronary artery disease (CAD), e.g., angina Canadian Class II-IV. In any
             patient in whom there is doubt, the patient should have a stress imaging study and, if
             abnormal, angiography to define whether or not CAD is present.

          -  An ECG recorded at screening showing evidence of cardiac ischemia (ST depression of ≥
             2 mm, measured from isoelectric line to the ST segment). If in any doubt, the patient
             should have a stress imaging study and, if abnormal, angiography to define whether or
             not CAD is present.

          -  Congestive heart failure (CHF) that meets New York Heart Association (NYHA) Class II
             to IV definitions and/or ejection fraction < 40% by multigated acquisition (MUGA) scan
             or < 50% by echocardiogram and/or magnetic resonance imaging (MRI);

          -  Hypertrophic cardiomegaly or restrictive cardiomyopathy from prior treatment or other
             causes.

          -  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.

          -  Patients requiring dual anti-platelets treatment for cardiac conditions or patients
             who are on anticoagulation for arterial or venous thrombosis. Patients with known
             psychiatric or substance abuse disorders that would interfere with cooperation with
             the requirements of the trial.

          -  Patients that are pregnant or breastfeeding, or expecting to conceive or father
             children within the projected duration of the trial, starting with the pre-screening
             or screening visit through at least 30 days after the last dose of trial treatment.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD)
Time Frame:2 years
Safety Issue:
Description:The estimated MTD would be the highest dose at which 0 out of 3 or 1 out of 6 subjects experience a dose-limiting toxicity (DLT), i.e. dose with an observed DLT rate of less than 0.33.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Changchun Deng

Trial Keywords

  • Hodgkin lymphoma (HL)
  • non-Hodgkin lymphoma (NHL)
  • Copanlisib
  • Romidepsin

Last Updated

January 15, 2020