Clinical Trials /

Safety and Efficacy Study of Loncastuximab Tesirine + Ibrutinib in Diffuse Large B-Cell or Mantle Cell Lymphoma

NCT03684694

Description:

The purpose of this Phase 1/2 study is to evaluate the safety and efficacy of Loncastuximab Tesirine (ADCT-402) in combination with Ibrutinib in participants with Advanced Diffuse Large B-Cell Lymphoma or Mantle Cell Lymphoma.

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
  • Mantle Cell Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Safety and Antitumor Activity Study of Loncastuximab Tesirine + Ibrutinib in Diffuse Large B-Cell or Mantle Cell Lymphoma
  • Official Title: A Phase 1b Open-Label Study to Evaluate the Safety and Antitumor Activity of Loncastuximab Tesirine and Ibrutinib in Patients With Advanced Diffuse Large B-Cell Lymphoma or Mantle Cell Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: ADCT-402-103
  • SECONDARY ID: 2018-002625-38
  • NCT ID: NCT03684694

Conditions

  • Diffuse Large B-Cell Lymphoma
  • Mantle Cell Lymphoma

Interventions

DrugSynonymsArms
Loncastuximab Tesirine and IbrutinibADCT-402 in combination with ibrutinibADCT-402

Purpose

The purpose of this Phase 1 study is to evaluate the safety and antitumor activity of Loncastuximab Tesirine (ADCT-402) and Ibrutinib in patients with Advanced Diffuse Large B-Cell Lymphoma or Mantle Cell Lymphoma.

Detailed Description

      This is a Phase 1b, open-label, single-arm combination study with a dose escalation phase
      (Part 1) followed by a dose expansion phase (Part 2). The study will enroll approximately 60
      patients.

      A standard 3+3 dose escalation design will be used for Part 1. The DLT period will be the 21
      days following the first dose of ibrutinib. The initial dose escalation cohort will receive
      loncastuximab tesirine for 2 cycles with concurrent ibrutinib (concomitant therapy) and may
      then continue ibrutinib therapy up to one year. Depending on the safety and tolerability of
      loncastuximab tesirine given concurrently with ibrutinib in the initial cohort, subsequent
      cohorts may receive either loncastuximab tesirine with concurrent ibrutinib or loncastuximab
      tesirine followed by ibrutinib (sequential therapy).

      Patients who have a response of PR or stable disease (SD) at the 14-week assessment may
      receive two additional doses of loncastuximab tesirine given 4 weeks apart.

      Part 2 will consist of up to two expansion cohorts, one for DLBCL and one for MCL. Each
      cohort will be 20 patients treated at the dose determined in Part 1.

      The study will include a Screening Period (of up to 28 days), a Treatment Period (cycles of 3
      to 4 weeks), and a Follow-up Period (approximately every 12 week visits for up to 2 years
      after treatment discontinuation).
    

Trial Arms

NameTypeDescriptionInterventions
ADCT-402ExperimentalA standard 3+3 dose escalation design will be used. The DLT period will be the 21 days following the first dose of ibrutinib. The initial dose escalation cohort will receive loncastuximab tesirine for 2 cycles with concurrent ibrutinib (concomitant therapy) and may then continue ibrutinib therapy up to one year. Depending on the safety and tolerability of loncastuximab tesirine given concurrently with ibrutinib in the initial cohort, subsequent cohorts may receive either loncastuximab tesirine with concurrent ibrutinib or loncastuximab tesirine followed by ibrutinib (sequential therapy).
  • Loncastuximab Tesirine and Ibrutinib

Eligibility Criteria

        Inclusion Criteria:

          1. Male or female patient aged 18 years or older

          2. Pathologic diagnosis of DLBCL, non-GCB subtype; or MCL

          3. Patients with DLBCL must have relapsed or refractory disease and have failed or been
             intolerant to available standard therapy

          4. Patients with MCL must have relapsed or refractory disease and have received at least
             one prior line of therapy

          5. Patients who have received previous CD19-directed therapy must have a biopsy which
             shows CD19 expression after completion of the CD19-directed therapy

          6. Measurable disease as defined by the 2014 Lugano Classification

          7. Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue block (or minimum
             10 freshly cut unstained slides if block is not available)

          8. ECOG performance status 0 to 2

          9. Screening laboratory values within the following parameters:

               1. Absolute neutrophil count (ANC) ≥1.0 × 103/µL (off growth factors at least 72
                  hours)

               2. Platelet count ≥75 × 103/µL without transfusion in the past 7 days

               3. Hemoglobin ≥8 g/dL (4.96 mmol/L), transfusion allowed

               4. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma
                  glutamyl transferase (GGT) ≤2.5 × the upper limit of normal (ULN); ≤5 × ULN if
                  there is liver involvement

               5. Total bilirubin ≤1.5 × ULN (patients with known Gilbert's syndrome may have a
                  total bilirubin up to ≤3 × ULN)

               6. Blood creatinine ≤1.5 × ULN or calculated creatinine clearance ≥60 mL/min by the
                  Cockcroft and Gault equation

         10. Negative beta-human chorionic gonadotropin (β-HCG) pregnancy test within 7 days prior
             to start of study drugs on C1D1 for women of childbearing potential

         11. Women of childbearing potential* must agree to use a highly effective** method of
             contraception from the time of giving informed consent until at least 16 weeks after
             the last dose of study therapy. Men with female partners who are of childbearing
             potential must agree that they will use a highly effective method of contraception
             from the time of giving informed consent until at least 16 weeks after the patient
             receives his last dose of study therapy

        Exclusion Criteria:

          1. Known history of hypersensitivity to or positive serum human ADA to a CD19 antibody

          2. Known history of hypersensitivity to ibrutinib

          3. Previous therapy with ibrutinib or other BTK inhibitors

          4. Previous therapy with loncastuximab tesirine

          5. Requires treatment or prophylaxis with a moderate or strong cytochrome P450 (CYP) 3A
             inhibitor

          6. Allogenic or autologous transplant within 60 days prior to start of study drugs (C1D1)

          7. Active graft-versus-host disease

          8. Post-transplantation lymphoproliferative disorder

          9. Active autoimmune disease, including motor neuropathy considered of autoimmune origin
             and other central nervous system (CNS) autoimmune disease

         10. Known seropositive and requiring anti-viral therapy for human immunodeficiency (HIV)
             virus, hepatitis B virus (HBV), or hepatitis C virus (HCV).

         11. History of Stevens-Johnson syndrome or toxic epidermal necrolysis

         12. Lymphoma with active CNS involvement at the time of screening, including
             leptomeningeal disease

         13. Clinically significant third space fluid accumulation (i.e., ascites requiring
             drainage or pleural effusion that is either requiring drainage or associated with
             shortness of breath)

         14. Breastfeeding or pregnant

         15. Significant medical comorbidities, including but not limited to, uncontrolled
             hypertension (blood pressure [BP] ≥160/100 mmHg repeatedly), unstable angina,
             congestive heart failure (greater than New York Heart Association class II),
             electrocardiographic evidence of acute ischemia, coronary angioplasty or myocardial
             infarction within 6 months prior to screening, uncontrolled atrial or ventricular
             cardiac arrhythmia, poorly controlled diabetes mellitus, or severe chronic pulmonary
             disease, or tuberculosis infection (tuberculosis screening based on local standards).

         16. Major surgery, radiotherapy, chemotherapy, or other anti-neoplastic therapy within 14
             days prior to start of study drugs (C1D1), except shorter if approved by the Sponsor

         17. Use of any other experimental medication within 14 days prior to start of study drugs
             (C1D1)

         18. Planned live vaccine administration after starting study drugs (C1D1)

         19. Any condition that could interfere with the absorption or metabolism of ibrutinib
             including malabsorption syndrome, disease significantly affecting gastrointestinal
             function, or resection of the stomach or small bowel

         20. Inherited or acquired bleeding disorders

         21. Ongoing anticoagulation with warfarin or equivalent vitamin K antagonists

         22. Failure to recover to Grade ≤1 (Common Terminology Criteria for Adverse Events [CTCAE]
             version 4.0) from acute non-hematologic toxicity (Grade ≤2 neuropathy or alopecia) due
             to previous therapy prior to screening

         23. Congenital long QT syndrome or a corrected QTcF interval of >480 ms at screening
             (unless secondary to pacemaker or bundle branch block)

         24. Active second primary malignancy other than non-melanoma skin cancers, non metastatic
             prostate cancer, in situ cervical cancer, ductal or lobular carcinoma in situ of the
             breast, or other malignancy that the Sponsor's medical monitor and Investigator agree,
             and document should not be exclusionary

         25. Any other significant medical illness, abnormality, or condition that would, in the
             Investigator's judgment, make the patient inappropriate for study participation or put
             the patient at risk
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of Adverse Events (AEs)
Time Frame:Up to 3.5 years
Safety Issue:
Description:AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product, which does not necessarily have to have a causal relationship with this treatment

Secondary Outcome Measures

Measure:Overall response rate (ORR)
Time Frame:Up to 2 years
Safety Issue:
Description:ORR according to the 2014 Lugano classification, defined as the proportion of patients with a best overall response (BOR) of complete response (CR) or partial response (PR)
Measure:Complete Response Rate (CR)
Time Frame:Up to 2 years
Safety Issue:
Description:CR rate defined as the percentage of treated patients with a BOR of CR
Measure:Duration of Response (DOR): time from first tumor response to disease progression or death
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:Overall survival (OS)
Time Frame:Up to 2 years
Safety Issue:
Description:Time between the start of treatment and death from any cause
Measure:Relapse-Free Survival (RFS)
Time Frame:Up to 2 years
Safety Issue:
Description:Time from the documentation of CR to disease progression or death
Measure:Progression-Free Survival
Time Frame:Up to 2 years
Safety Issue:
Description:Time between start of treatment and the first documentation of progression, or death
Measure:Time to Reach Maximum Concentration (Tmax) of Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199)
Time Frame:Day 1 (pre-dose, end of infusion and 4 hours post-dose), Day 8 and Day 15 of Cycles 1 and 2 (Cycle length is 3 weeks) and Day 1 of Cycle 3 onwards (Cycle length is 4 weeks)
Safety Issue:
Description:
Measure:Maximum Observed Concentration (Cmax) of Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199)
Time Frame:Day 1 (pre-dose, end of infusion and 4 hours post-dose), Day 8 and Day 15 of Cycles 1 and 2 (Cycle length is 3 weeks) and Day 1 of Cycle 3 onwards (Cycle length is 4 weeks)
Safety Issue:
Description:
Measure:Area Under the Concentration-Time Curve from Time Zero to the Last Quantifiable Concentration (AUC0-last) of Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199)
Time Frame:Day 1 (pre-dose, end of infusion and 4 hours post-dose), Day 8 and Day 15 of Cycles 1 and 2 (Cycle length is 3 weeks) and Day 1 of Cycle 3 onwards (Cycle length is 4 weeks)
Safety Issue:
Description:
Measure:Area Under the Concentration-Time Curve from Time Zero to the End of the Dosing Interval (AUC0-τ) of Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199)
Time Frame:Day 1 (pre-dose, end of infusion and 4 hours post-dose), Day 8 and Day 15 of Cycles 1 and 2 (Cycle length is 3 weeks) and Day 1 of Cycle 3 onwards (Cycle length is 4 weeks)
Safety Issue:
Description:
Measure:Area Under the Concentration-Time Curve from Time Zero to Infinity (AUC0-∞) of Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199)
Time Frame:Day 1 (pre-dose, end of infusion and 4 hours post-dose), Day 8 and Day 15 of Cycles 1 and 2 (Cycle length is 3 weeks) and Day 1 of Cycle 3 onwards (Cycle length is 4 weeks)
Safety Issue:
Description:
Measure:Clearance (CL) of Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199)
Time Frame:Day 1 (pre-dose, end of infusion and 4 hours post-dose), Day 8 and Day 15 of Cycles 1 and 2 (Cycle length is 3 weeks) and Day 1 of Cycle 3 onwards (Cycle length is 4 weeks)
Safety Issue:
Description:
Measure:Accumulation Index (AI) Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199)
Time Frame:Day 1 (pre-dose, end of infusion and 4 hours post-dose), Day 8 and Day 15 of Cycles 1 and 2 (Cycle length is 3 weeks) and Day 1 of Cycle 3 onwards (Cycle length is 4 weeks)
Safety Issue:
Description:
Measure:Number of Participants with Anti-Drug Antibody (ADA) Titers to Loncastuximab Tesirine
Time Frame:Day 1 and Day 15 of Cycles 1 and 2 (Cycle length is 3 weeks) and Day 1 of Cycle 3 onwards (Cycle length is 4 weeks)
Safety Issue:
Description:Followed by characterization and evaluation of neutralizing capacity as needed.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:ADC Therapeutics S.A.

Trial Keywords

  • Loncastuximab Tesirine in Combination with Ibrutinib

Last Updated

January 23, 2020