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Diffuse Large B-Cell LymphomaPhase 1NCT03685344

Safety and Antitumor Activity Study of Loncastuximab Tesirine and Durvalumab in Diffuse Large B-Cell, Mantle Cell, or Follicular Lymphoma

A Phase 1 study testing Loncastuximab Tesirine and Durvalumab in people with Diffuse Large B-Cell Lymphoma and Mantle Cell Lymphoma, run by ADC Therapeutics S.A. at 14 sites in 2 countries.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

The purpose of this phase 1 study is to evaluate the safety and anti-tumor activity of Loncastuximab Tesirine (ADCT-402) and Durvalumab in participants with Advanced Diffuse Large B-Cell Lymphoma, Mantle Cell Lymphoma, or Follicular Lymphoma Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Loncastuximab Tesirine and Durvalumab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
13 participants
Where
14 sitesin 2 countries
Study dates
4 Feb 2019to 27 Oct 2020
Phase
Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Male or female participants aged 18 years or older
  • Pathologic diagnosis of DLBCL, MCL, or FL
  • Participants must have relapsed or refractory disease and have failed or been intolerant to standard therapy
  • Participants who have received previous CD19-directed therapy must have a biopsy that shows CD19 expression after completion of the CD19-directed therapy
  • Measurable disease as defined by the 2014 Lugano Classification
  • Participants must be willing to undergo tumor biopsy
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  • ECOG performance status 0-1
  • Screening laboratory values within the following parameters:
  • Absolute neutrophil count (ANC) ≥1.0 × 103/µL (off growth factors at least 72 hours)
  • Platelet count ≥75 × 103/µL without transfusion in the past 7 days
  • Hemoglobin ≥9.0 g/dL (5.59 mmol/L), transfusion allowed
  • Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and GGT ≤2.5 × the upper limit of normal (ULN)
  • Total bilirubin ≤1.5 × ULN (participants with known Gilbert's syndrome may have a total bilirubin up to ≤3 × ULN)
  • Blood creatinine ≤1.5 × ULN or calculated creatinine clearance ≥60 mL/min by the Cockcroft-Gault equation
  • Negative beta-human chorionic gonadotropin (β-HCG) pregnancy test within 3 days prior to start of study drug on C1D1 for women of childbearing potential
  • 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

Who cannot join

  • Known history of hypersensitivity to or positive serum human ADA to a CD19 antibody.
  • Previous therapy with any checkpoint inhibitor
  • Autologous stem cell transplant within 100 days prior to start of study drug (C1D1)
  • History of allogenic stem cell transplant
  • History of solid organ transplant
  • Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion:
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  • Participants with vitiligo or alopecia
  • Participants with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
  • Any chronic skin condition that does not require systemic therapy
  • Participants without active disease in the last 5 years may be included but only after consultation with the Study Physician
  • Participants with celiac disease controlled by diet alone
  • Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice)
  • Known seropositive and requiring anti-viral therapy for human immunodeficiency (HIV) virus, hepatitis B virus (HBV), or hepatitis C virus (HCV)
  • History of Stevens-Johnson syndrome or toxic epidermal necrolysis
  • Lymphoma with active central nervous system (CNS) involvement at the time of screening, including leptomeningeal disease
  • 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)
  • Breastfeeding or pregnant
  • 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, or severe chronic pulmonary disease
  • Radiotherapy, chemotherapy, or other anti-neoplastic therapy within 14 days prior to start of study drug (C1D1), except shorter if approved by the Sponsor.
  • Major surgery within 28 days prior to start of study drug (C1D1), except shorter if approved by the Sponsor. Note: Local surgery of isolated lesions for palliative intent is acceptable.
  • Use of any other experimental medication within 14 days prior to start of study drug (C1D1)
  • Planned live vaccine administration after starting study drug (C1D1)
  • 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.
  • Congenital long QT syndrome or a corrected QTcF interval of >470 ms at screening (unless secondary to pacemaker or bundle branch block)
  • History of another primary malignancy except for:
  • Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of investigational product and of low potential risk for recurrence
  • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
  • Adequately treated carcinoma in situ without evidence of disease 21. History of active primary immunodeficiency
  • History of active primary immunodeficiency or any other significant medical illness, abnormality, or condition that would, in the Investigator's judgement, make the patient inappropriate for study participation or put the participant at risk.

Trial locations and contacts

14 sites in 2 countries.

14 sites in 2 countries

United States9 sites

  • University of Alabama at Birmingham

    Birmingham, Alabama, 35294

  • UCH-MHS Memorial Hospital Centeral

    Colorado Springs, Colorado, 80909

  • Baylor University Medical Center

    Dallas, Texas, 75246

  • University of Florida Health Shands Cancer Hospital

    Gainesville, Florida, 32603

  • Joe Arrington Cancer Research and Treatment Center

    Lubbock, Texas, 79410

  • University of Miami - Sylvester Comprehensive Cancer Center

    Miami, Florida, 33136

  • Rutgers Cancer Institute of New Jersey

    New Brunswick, New Jersey, 08901

  • Icahm School of Medicine at Mount Sinai

    New York, New York, 10029

  • Baylor Scott & White Medical Center - Temple

    Temple, Texas, 76508

Other trials in United States

Spain5 sites

  • Hospital Clinic de Barcelona

    Barcelona, 08036

  • Hospital General Universitario Gregorio Marañon Pabellón de Oncología

    Madrid, 28009

  • Hospital Universitario Fundación Jiménez Díaz Unidad de Limfomas Servicio de Hematologia

    Madrid, 28040

  • Hospital Universitario Virgen Macarena Servicio Oncologia Medica

    Seville, 41009

  • Hospital Universitario Virgen Del Rocio

    Seville, 41015

Other trials in Spain

About this study

Official title: A Phase 1 Open-Label Study to Evaluate the Safety and Antitumor Activity of Loncastuximab Tesirine and Durvalumab in Patients With Advanced Diffuse Large B-Cell Lymphoma, Mantle Cell Lymphoma, or Follicular Lymphoma

The purpose of this phase 1 study is to evaluate the safety and anti-tumor activity of Loncastuximab Tesirine (ADCT-402) and Durvalumab in participants with Advanced Diffuse Large B-Cell Lymphoma, Mantle Cell Lymphoma, or Follicular Lymphoma

Read the 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 75 participants.

A standard 3+3 dose escalation design will be used for Part 1. The DLT period will be the 21 days after the first durvalumab dose.

Part 2 will consist of up to 3 expansion cohorts, one for DLBCL, one for MCL, and one for FL. Each cohort will be approximately 20 participants 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, 6, and 4 weeks), and a Follow-up Period (approximately every 12 week visits for up to 2 years after treatment discontinuation).

Being tested
Loncastuximab Tesirine and Durvalumab
Keywords
Loncastuximab Tesirine in Combination with Durvalumab
Medical subject headings
Lymphoma, Large B-Cell, Diffuse, Lymphoma, Mantle-Cell, Lymphoma, Follicular

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Loncastuximab Tesirine and DurvalumabDrug

    Also called ADCT-402 in combination with Durvalumab, Zynlonta

    intravenous infusion

Study groups in NCT03685344
Study groupRoleWhat they receive
ADCT-402ExperimentalDose escalation phase: Ascending doses of Loncastuximab tesirine will be administered using a traditional 3+3 design. Dose level 1: 90 µg/kg, every 3 weeks (Q3W). Dose level 2: 120 µg/kg, Q3W. Dose level 3: 150 µg/kg, Q3W. Loncastuximab tesirine will be given for 2 doses, 3 weeks apart. Dose expansion phase: Loncastuximab tesirine will be administered at the recommended dose determined in the dose escalation phase. Durvalumab will also be administered at a dose of 1500 mg once every 4 weeks (Q4W) throughout the dose escalation phase and dose expansion phase.
Receives: Drug: Loncastuximab Tesirine and Durvalumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Number of Participants With a Treatment-emergent Adverse Event (TEAE)

    A TEAE was defined as an adverse event (AE) that occurred or worsened in the period extending from the first dose of study drugs to 30 days after the last dose of study drugs or initiation of new anti-cancer therapy (whichever occurred earlier).

    Evaluation of TEAEs included the number of participants with at least one: TEAE, serious TEAE and grade ≥3 TEAE as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

    CTCAE grading scale:

    • Grade 3 = Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living.
    • Grade 4 = Life-threatening consequences; urgent intervention indicated.
    • Grade 5 = Death related to AE.

    Clinically significant changes from baseline for safety laboratory values, vital sign measurements and electrocardiograms (ECGs) were recorded as TEAEs.

    Measured: Day 1 to 30 days after the last dose of study drugs (maximum treatment duration at study termination was 336 days)

  2. Number of Participants With a Dose-limiting Toxicity

    DLTs were defined as specific events which occurred in the 21-day DLT evaluation period of the dose escalation part, except any events that were clearly due to underlying disease or extraneous causes. The grading and severity of events were based on the guidelines provided in the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

    Measured: 21 days after first dose of durvalumab (Day 8 to Day 29)

  3. Number of Participants With a Treatment-emergent Adverse Event Leading to Dose Interruption or Reduction

    Measured: Day 1 to end of treatment (maximum treatment duration at study termination was 336 days)

  4. Number of Participants With Changes From Baseline on the Eastern Cooperative Oncology Group (ECOG) Performance Status

    Eastern Cooperative Oncology Group (ECOG) performance status was scored on a 6-point scale where higher scores indicate a worse outcome. ECOG scores included the following:

    • 0 = fully active, able to carry on all pre-disease performance without restriction
    • 1 = restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work
    • 2 = ambulatory and capable of all self-care but unable to carry out any work activities; up and about more than 50% of waking hours
    • 3 = capable of only limited self-care; confined to bed or chair more than 50% of waking hours
    • 4 = completely disabled; cannot carry on any self-care; totally confined to bed or chair
    • 5 = dead

    Measured: Day 1 to end of treatment (maximum treatment duration at study termination was 336 days)

Secondary outcomes (14)

  1. Overall Response Rate (ORR)

    ORR according to the 2014 Lugano classification as determined by the investigator. Overall response rate was the percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR).

    CR was defined as achieving each of the following:

    • Complete metabolic response.
    • Complete radiologic response (target node regress to <1.5 cm, no non-measured lesions, no organ enlargement, no new lesions and normal bone marrow morphology).

    PR was defined as achieving each of the following:

    • Partial metabolic response (findings indicate residual disease).
    • Partial remission (>50% decrease in target measurable nodes, regression/ absence/ no increase of non-measured lesions, spleen regressed by >50% in length and no new lesions).

    Measured: Up to 1.5 years

  2. Duration of Response (DOR)

    DOR was defined as the time from the documentation of first tumor response (CR or PR) to disease progression or death.

    CR was defined as achieving each of the following:

    • Complete metabolic response.
    • Complete radiologic response (target node regress to <1.5 cm, no non-measured lesions, no organ enlargement, no new lesions and normal bone marrow morphology).

    PR was defined as achieving each of the following:

    • Partial metabolic response (findings indicate residual disease).
    • Partial remission (>50% decrease in target measurable nodes, regression/ absence/ no increase of non-measured lesions, spleen regressed by >50% in length and no new lesions).

    Measured: Up to 1.5 years

  3. Complete Response Rate (CRR)

    CRR was defined as the percentage of participants with a BOR of CR, according to the 2014 Lugano classification, as determined by the investigator.

    CR was defined as achieving each of the following:

    • Complete metabolic response.
    • Complete radiologic response (target node regress to <1.5 cm, no non-measured lesions, no organ enlargement, no new lesions and normal bone marrow morphology).

    Measured: Up to 1.5 years

  4. Relapse-free Survival (RFS)

    RFS was defined as the time from the documentation of CR to disease progression or death.

    CR was defined as achieving each of the following:

    • Complete metabolic response.
    • Complete radiologic response (target node regress to <1.5 cm, no non-measured lesions, no organ enlargement, no new lesions and normal bone marrow morphology).

    Disease progression was defined as progressive metabolic disease and one of the following:

    • Target node progression.
    • An individual extranodal lesion must be abnormal with length > 1.5cm and/or increase of length > 50%.
    • New or clear progression of non-measured lesions.
    • Regrowth of previously resolved lesions or new nodes >1.5 cm in length.
    • New or recurrent bone marrow involvement.

    Measured: Up to 1.5 years

  5. Progression-free Survival (PFS)

    PFS was defined as the time between start of treatment and the first documentation of progression, or death.

    Disease progression was defined as progressive metabolic disease and one of the following:

    • Target node progression.
    • An individual extranodal lesion must be abnormal with length > 1.5cm and/or increase of length > 50%.
    • New or clear progression of non-measured lesions.
    • Regrowth of previously resolved lesions or new nodes >1.5 cm in length.
    • New or recurrent bone marrow involvement.

    Measured: Up to 1.5 years

  6. Overall Survival (OS)

    OS was defined as the time between the start of treatment and death from any cause.

    Measured: Up to 1.5 years

  7. Maximum Concentration (Cmax) of Loncastuximab Tesirine Conjugated Antibody, Total Antibody and Warhead SG3199

    Cmax of loncastuximab tesirine conjugated antibody and total antibody was calculated for Cycles 1 and 2. Cmax of warhead SG3199 was only calculated for Cycle 1 as data was not collected for Cycle 2.

    Measured: Cycles 1 and 2 (where Cycle 1 was 4 weeks long and Cycle 2 was 6 weeks long): Day 1 pre-dose and at 0.5 and 4 hours post-dose, Day 8 and Day 15

  8. Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUC0-last) of Loncastuximab Tesirine Conjugated Antibody, Total Antibody and Warhead SG3199

    AUC0-last of loncastuximab tesirine conjugated antibody and total antibody was calculated for Cycles 1 and 2. AUC0-last of warhead SG3199 was only calculated for Cycle 1 as data was not collected for Cycle 2.

    Measured: Cycles 1 and 2 (where Cycle 1 was 4 weeks long and Cycle 2 was 6 weeks long): Day 1 pre-dose and at 0.5 and 4 hours post-dose, Day 8 and Day 15

  9. Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) of Loncastuximab Tesirine Conjugated Antibody, Total Antibody and Warhead SG3199

    AUCinf of loncastuximab tesirine conjugated antibody and total antibody was calculated for Cycles 1 and 2. AUCinf of warhead SG3199 was only calculated for Cycle 1 as data was not collected for Cycle 2.

    Measured: Cycles 1 and 2 (where Cycle 1 was 4 weeks long and Cycle 2 was 6 weeks long): Day 1 pre-dose and at 0.5 and 4 hours post-dose, Day 8 and Day 15

  10. Apparent Terminal Half-life (Thalf) of Loncastuximab Tesirine Conjugated Antibody, Total Antibody and Warhead SG3199

    Thalf of loncastuximab tesirine conjugated antibody and total antibody was calculated for Cycles 1 and 2. Thalf of warhead SG3199 was only calculated for Cycle 1 as data was not collected for Cycle 2.

    Measured: Cycles 1 and 2 (where Cycle 1 was 4 weeks long and Cycle 2 was 6 weeks long): Day 1 pre-dose and at 0.5 and 4 hours post-dose, Day 8 and Day 15

  11. Apparent Clearance (CL) of Loncastuximab Tesirine Conjugated Antibody, Total Antibody and Warhead SG3199

    CL for Cycle 2 reflects steady-state clearance. CL of loncastuximab tesirine conjugated antibody and total antibody was calculated for Cycles 1 and 2.

    Measured: Cycles 1 and 2 (where Cycle 1 was 4 weeks long and Cycle 2 was 6 weeks long): Day 1 pre-dose and at 0.5 and 4 hours post-dose, Day 8 and Day 15

  12. Apparent Volume of Distribution at Steady State (Vss) of Loncastuximab Tesirine Conjugated Antibody, Total Antibody and Warhead SG3199

    Vss of loncastuximab tesirine conjugated antibody and total antibody was calculated for Cycles 1 and 2.

    Measured: Cycles 1 and 2 (where Cycle 1 was 4 weeks long and Cycle 2 was 6 weeks long): Day 1 pre-dose and at 0.5 and 4 hours post-dose, Day 8 and Day 15

  13. Accumulation Index (AI) of Loncastuximab Tesirine Conjugated Antibody and Total Antibody

    AI is the ratio of drug accumulation after repeated administration compared to a single dose. AI of loncastuximab tesirine conjugated antibody and total antibody was calculated from Cycles 1 and 2.

    Measured: Cycles 1 and 2 (where Cycle 1 was 4 weeks long and Cycle 2 was 6 weeks long): Day 1 pre-dose and at 0.5 and 4 hours post-dose, Day 8 and Day 15

  14. Number of Participants With an Anti-drug Antibody (ADA) Response to Loncastuximab Tesirine

    Detection of ADAs were performed by using a screening assay for identification of antibody positive samples/patients, a confirmation assay, and titer assessment, and were performed using the Meso-Scale Discovery Electrochemiluminescence platform.

    Measured: Cycle 1 (= 3 weeks): Day 1 pre-dose & Day 15; Cycles 2, 3, 5, 6, & 7 (Cycle 2 = 6 weeks, other cycles = 4 weeks): Day 1 pre-dose; 30 days after last dose of study drugs

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted26 Sep 2018
  2. Study start4 Feb 2019
  3. Primary completion27 Oct 2020
  4. Study completion27 Oct 2020

Why it stopped: In a limited number of patients, no additional activity was evident for the combination vs. loncastuximab tesirine monotherapy.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Sequential
Masking
None (open label)
Enrolment
13 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03685344
Sponsor's protocol ID
ADCT-402-104
Other IDs
2018-002670-43, 2018
Status last verified
Sep 2021
First submitted
11 Sep 2018
Last updated
26 Oct 2021
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Loncastuximab Tesirine and Durvalumab in people with Diffuse Large B-Cell Lymphoma and Mantle Cell Lymphoma, run by ADC Therapeutics S.A. at 14 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 16 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 26 Oct 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 14 sites in United States, Spain. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 26 Oct 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Participants With a Treatment-emergent Adverse Event (TEAE) (time frame: Day 1 to 30 days after the last dose of study drugs (maximum treatment duration at study termination was 336 days)). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03685344.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Oct 2021.

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