A Study to Evaluate the Safety and Anti-cancer Activity of Loncastuximab Tesirine in Combination With Other Anti-cancer Agents in Participants With Relapsed or Refractory B-cell Non-Hodgkin Lymphoma (LOTIS 7)
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| ClinicalTrials.gov Identifier: NCT04970901 |
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Recruitment Status :
Recruiting
First Posted : July 21, 2021
Last Update Posted : February 24, 2023
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| B-Cell Non-Hodgkin Lymphoma Relapsed B-Cell Non-Hodgkin Lymphoma Refractory B-Cell Non-Hodgkin Lymphoma | Drug: Loncastuximab Tesirine Drug: Gemcitabine Drug: Lenalidomide Drug: Polatuzumab Vedotin Drug: Umbralisib | Phase 1 |
This is a Phase 1b, multi-center, open-label, multi-arm study to evaluate the safety and anti-cancer activity of loncastuximab tesirine in combination with gemcitabine, lenalidomide, polatuzumab vedotin, or umbralisib in participants with relapsed or refractory B-cell Non-Hodgkin Lymphoma (R/R B-NHL) including diffuse large B-cell lymphoma (DLBCL), high grade B cell lymphoma (HGBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), Burkitt lymphoma (BL). The study will enroll approximately 200 participants. Loncastuximab tesirine (ADCT-402; Zynlonta) is an antibody drug conjugate (ADC), composed of a humanized monoclonal antibody directed against human cluster of differentiation 19 (CD19) conjugated through a cathepsin-cleavable linker to a pyrrolobenzodiazepine (PBD) dimer cytotoxin. Loncastuximab tesirine has been granted by Food and Drug Administration (FDA) as accelerated approval for adult participants with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including DLBCL not otherwise specified, DLBCL arising from low grade lymphoma, and HGBCL. The study includes multiple arms in two parts, Dose Escalation part (Part 1) and Dose Expansion part (Part 2). Part 2 may include DLBCL, HGBCL, FL, MCL, MZL, and BL cohorts. A Dose-Escalating Steering Committee (DESC) is responsible for safety monitoring and overall supervision of the study. Part 1 will use a standard 3+3 dose escalation design and Part 2 subpopulations of B-cell non-Hodgkin lymphomas with specific combination/dose levels will be determined from data collected in Part 1.
For each participant, the study will include a Screening Period (of up to 28 days), a Treatment Period (cycles of 21 days), and a Follow-up Period (approximately every 12 week visits for up to two years). Participants may continue treatment for up to one year or until disease progression, unacceptable toxicity, or other discontinuation criteria, whichever occurs first.
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 200 participants |
| Allocation: | Non-Randomized |
| Intervention Model: | Sequential Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | A Phase 1b Open-Label Study to Evaluate the Safety and Anti-cancer Activity of Loncastuximab Tesirine in Combination With Other Anti-cancer Agents in Patients With Relapsed or Refractory B-cell Non-Hodgkin Lymphoma (LOTIS 7) |
| Actual Study Start Date : | June 17, 2022 |
| Estimated Primary Completion Date : | February 12, 2025 |
| Estimated Study Completion Date : | February 10, 2026 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Part 1 (Dose Escalation): Loncastuximab Tesirine + Gemcitabine (Arm A)
Participants will receive loncastuximab tesirine on Day 1 of each cycle at a dose of 150 μg/kg for two cycles, then 75 μg/kg for subsequent cycles (where each cycle is 21 days). Participants will also receive escalating doses (500 mg/m^2 to 1000 mg/m^2) of gemcitabine on Day 1 of each cycle (where each cycle is 21 days). Not currently enrolling. |
Drug: Loncastuximab Tesirine
Intravenous (IV) infusion
Other Names:
Drug: Gemcitabine Intravenous (IV) infusion |
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Experimental: Part 1 (Dose Escalation): Loncastuximab Tesirine + Lenalidomide (Arm B)
Participants will receive loncastuximab tesirine on Day 1 of each cycle at a dose of 150 μg/kg for two cycles, then 75 μg/kg for subsequent cycles (where each cycle is 21 days). Participants will also receive escalating doses (15 mg to 25 mg) of lenalidomide once daily on a 2 weeks on and 1 week off schedule, starting on Day 1 of each cycle (where each cycle is 21 days). Not currently enrolling. |
Drug: Loncastuximab Tesirine
Intravenous (IV) infusion
Other Names:
Drug: Lenalidomide Orally via capsules |
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Experimental: Part 1 (Dose Escalation): Loncastuximab Tesirine + Polatuzumab Vedotin (Arm C)
Participants will receive escalating doses (90 µg/kg to 150 µg/kg) of loncastuximab tesirine on Day 1 of each cycle (where each cycle is 21 days). Participants will also receive polatuzumab vedotin at a dose of 1.8 mg/kg on Day 1 of each cycle (where each cycle is 21 days).
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Drug: Loncastuximab Tesirine
Intravenous (IV) infusion
Other Names:
Drug: Polatuzumab Vedotin Intravenous (IV) infusion |
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Experimental: Part 1 (Dose Escalation): Loncastuximab Tesirine + Umbralisib (Arm D)
Participants will receive loncastuximab tesirine on Day 1 of each cycle at a dose of 150 μg/kg for two cycles, then 75 μg/kg for subsequent cycles (where each cycle is 21 days). Participants will also receive escalating doses (600 mg to 800 mg) of umbralisib once daily, starting on Day 1 of each cycle (where each cycle is 21 days). Not currently enrolling. |
Drug: Loncastuximab Tesirine
Intravenous (IV) infusion
Other Names:
Drug: Umbralisib Orally via tablets |
|
Experimental: Part 2 (Dose Expansion): Loncastuximab Tesirine + Gemcitabine (Arm A)
Participants with subpopulation of non-Hodgkin lymphomas (NHLs) (diffuse large B-cell lymphoma [DLBCL], high grade B cell lymphoma [HGBCL], follicular lymphoma [FL], mantle cell lymphoma [MCL], marginal zone lymphoma [MZL], and Burkitt lymphoma [BL] cohorts) will receive loncastuximab tesirine in combination with gemcitabine at the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) if favorable results of Part 1 are received. Not currently enrolling. |
Drug: Loncastuximab Tesirine
Intravenous (IV) infusion
Other Names:
Drug: Gemcitabine Intravenous (IV) infusion |
|
Experimental: Part 2 (Dose Expansion): Loncastuximab Tesirine + Lenalidomide (Arm B)
Participants with subpopulation of non-Hodgkin lymphomas (NHLs) (diffuse large B-cell lymphoma [DLBCL], high grade B cell lymphoma [HGBCL], follicular lymphoma [FL], mantle cell lymphoma [MCL], marginal zone lymphoma [MZL], and Burkitt lymphoma [BL] cohorts) will receive loncastuximab tesirine in combination with lenalidomide at the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) if favorable results of Part 1 are received. Not currently enrolling. |
Drug: Loncastuximab Tesirine
Intravenous (IV) infusion
Other Names:
Drug: Lenalidomide Orally via capsules |
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Experimental: Part 2 (Dose Expansion): Loncastuximab Tesirine + Polatuzumab Vedotin (Arm C)
Participants with subpopulation of non-Hodgkin lymphomas (NHLs) (diffuse large B-cell lymphoma [DLBCL], high grade B cell lymphoma [HGBCL], follicular lymphoma [FL], mantle cell lymphoma [MCL], marginal zone lymphoma [MZL], and Burkitt lymphoma [BL] cohorts) will receive loncastuximab tesirine in combination with polatuzumab vedotin at the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) if favorable results of Part 1 are received. Not currently enrolling. |
Drug: Loncastuximab Tesirine
Intravenous (IV) infusion
Other Names:
Drug: Polatuzumab Vedotin Intravenous (IV) infusion |
|
Experimental: Part 2 (Dose Expansion): Loncastuximab Tesirine + Umbralisib (Arm D)
Participants with subpopulation of non-Hodgkin lymphomas (NHLs) (diffuse large B-cell lymphoma [DLBCL], high grade B cell lymphoma [HGBCL], follicular lymphoma [FL], mantle cell lymphoma [MCL], marginal zone lymphoma [MZL], and Burkitt lymphoma [BL] cohorts) will receive loncastuximab tesirine in combination with umbralisib at the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) if favorable results of Part 1 are received. Not currently enrolling. |
Drug: Loncastuximab Tesirine
Intravenous (IV) infusion
Other Names:
Drug: Umbralisib Orally via tablets |
- Number of Participants Who Experience a Treatment-emergent Adverse Event (TEAE) [ Time Frame: Up to approximately 2 years ]Frequency and severity of TEAEs and treatment-emergent serious adverse events (TESAEs). TEAEs and TESAEs will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.
- Number of Participants Who Experience a Dose-Limiting Toxicity (DLT) [ Time Frame: Day 1 to Day 21 of Cycle 1, where a cycle is 21 days ]
- Number of Participants Who Experience an Adverse Event (AE) Leading to Dose Delay [ Time Frame: Up to approximately 1 year ]
- Number of Participants Who Experience an Adverse Event (AE) Leading to Dose Interruption [ Time Frame: Up to approximately 1 year ]
- Number of Participants Who Experience an Adverse Event (AE) Leading to Dose Reduction [ Time Frame: Up to approximately 1 year ]
- Number of Participants Who Experience a Clinically Significant Change from Baseline in Safety Laboratory Measurements [ Time Frame: Baseline up to approximately 1 year ]
- Number of Participants Who Experience a Clinically Significant Change from Baseline in Vital Signs [ Time Frame: Baseline up to approximately 1 year ]
- Number of Participants Who Experience a Clinically Significant Change from Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status [ Time Frame: Baseline up to approximately 1 year ]ECOG performance status will be measured on a scale from grades 0-5, where a higher grade indicates a worse outcome.
- Number of Participants Who Experience a Clinically Significant Change from Baseline in 12-Lead Electrocardiogram (ECG) Measurements [ Time Frame: Baseline up to approximately 1 year ]
- Overall Response Rate (ORR) [ Time Frame: Up to approximately 2 years ]
- Duration of Response (DOR) [ Time Frame: Up to approximately 2 years ]
- Complete Response Rate (CRR) [ Time Frame: Up to approximately 2 years ]
- Progression-Free Survival (PFS) [ Time Frame: Up to approximately 2 years ]
- Relapse-Free Survival (RFS) [ Time Frame: Up to approximately 2 years ]
- Overall Survival (OS) [ Time Frame: Up to approximately 2 years ]
- Average Concentration of Loncastuximab Tesirine [ Time Frame: Day 1 to end of treatment (up to approximately 1 year) ]
- Maximum Concentration (Cmax) of Loncastuximab Tesirine [ Time Frame: Day 1 to end of treatment (up to approximately 1 year) ]
- Time to Maximum Concentration (Tmax) of Loncastuximab Tesirine [ Time Frame: Day 1 to end of treatment (up to approximately 1 year) ]
- Area Under the Concentration-Time Curve from Time Zero to the Last Quantifiable Concentration (AUClast) of Loncastuximab Tesirine [ Time Frame: Day 1 to end of treatment (up to approximately 1 year) ]
- Area Under the Concentration-Time Curve from Time Zero to the End of the Dosing Interval (AUCtau) of Loncastuximab Tesirine [ Time Frame: Day 1 to end of treatment (up to approximately 1 year) ]
- Area Under the Concentration-Time Curve from Time Zero to Infinity (AUCinf) of Loncastuximab Tesirine [ Time Frame: Day 1 to end of treatment (up to approximately 1 year) ]
- Apparent Terminal Elimination Half-Life (Thalf) of Loncastuximab Tesirine [ Time Frame: Day 1 to end of treatment (up to approximately 1 year) ]
- Apparent Clearance (CL) of Loncastuximab Tesirine [ Time Frame: Day 1 to end of treatment (up to approximately 1 year) ]
- Apparent Steady-State Volume of Distribution (Vss) of Loncastuximab Tesirine [ Time Frame: Day 1 to end of treatment (up to approximately 1 year) ]
- Accumulation Index (AI) of Loncastuximab Tesirine [ Time Frame: Day 1 to end of treatment (up to approximately 1 year) ]
- Number of Participants With Anti-Drug Antibody (ADA) Titers to Loncastuximab Tesirine [ Time Frame: Day 1 to end of treatment (up to approximately 1 year) ]
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Male or female participant aged 18 years or older
- Pathologic diagnosis of relapsed (disease that has recurred following a response) or refractory (disease that failed to respond to prior therapy) B-cell non-Hodgkin Lymphoma (B-NHL) (2016 World Health Organization classification) who have failed, or been intolerant to any approved therapy and had received at least two systemic treatment regimens
- Participants who have received previous cluster of differentiation 19 (CD19)-directed therapy must have a biopsy that shows CD19 expression after completion of the CD19-directed therapy
- Need of systemic treatment for any of the listed indications as assessed by the investigator, including indolent B-NHLs (e.g. follicular lymphoma [FL] and marginal zone lymphoma [MZL])
- Measurable disease as defined by the 2014 Lugano Classification
- Availability of formalin-fixed paraffin-embedded tumor tissue block
- Eastern Cooperative Oncology Group performance status 0 to 2
- Adequate organ function
- Women of childbearing potential (WOCBP) must agree to use a highly effective method of contraception from the time of giving informed consent (for the arm that includes lenalidomide, from at least 4 weeks before starting lenalidomide) until at least 9 months after the last dose of study drug. Men with female partners who are of childbearing potential must agree to use a highly effective method of contraception from the time of giving informed consent until at least 6 months after the last dose of study drug
Exclusion Criteria:
- Known history of hypersensitivity resulting in treatment discontinuation to or positive serum human anti-drug antibody (ADA) to a CD19 antibody
- Known history of hypersensitivity to gemcitabine, lenalidomide, polatuzumab vedotin, or umbralisib leading to treatment discontinuation (applied to relevant arm and/or cohort of the specific drug administered)
- Previous therapy with loncastuximab tesirine
- Previous treatment of gemcitabine, lenalidomide, polatuzumab vedotin or umbralisib (applied to relevant arm and/or cohort of the specific drug administered)
- Allogenic or autologous stem cell transplant within 60 days prior to start of study drug Cycle 1, Day 1 (C1D1) (cycle is 21 days)
- Human immunodeficiency virus (HIV) seropositive
- Serologic evidence of chronic hepatitis B virus (HBV) infection and unable or unwilling to receive standard prophylactic antiviral therapy or with detectable HBV viral load
- Serologic evidence of hepatitis C virus (HCV) infection without completion of curative treatment or with detectable HCV viral load
- For the arm that includes umbralisib, confirmed cytomegalovirus (CMV) infection (participants who are CMV immunoglobulin G [IgG] or immunoglobulin M [IgM] positive but CMV deoxyribonucleic acid [DNA] negative by polymerase chain reaction [PCR] are eligible)
- For the arm that includes umbralisib, history of or ongoing inflammatory bowel disease
- 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
- Major surgery, radiotherapy, chemotherapy, or other anti-neoplastic therapy, within 14 days prior to start of study drugs (C1D1; cycle is 21 days), except shorter if approved by the Sponsor
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): NCT04970901
| Contact: Contact ADC Therapeutics | 954-903-7994 | clinical.trials@adctherapeutics.com |
Show 26 study locations
| Responsible Party: | ADC Therapeutics S.A. |
| ClinicalTrials.gov Identifier: | NCT04970901 |
| Other Study ID Numbers: |
ADCT-402-105 2021-001071-16 ( EudraCT Number ) |
| First Posted: | July 21, 2021 Key Record Dates |
| Last Update Posted: | February 24, 2023 |
| Last Verified: | February 2023 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | No |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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B-Cell Non-Hodgkin Lymphoma Relapsed B-Cell Non-Hodgkin Lymphoma Refractory B-Cell Non-Hodgkin Lymphoma Loncastuximab Tesirine |
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Lymphoma Lymphoma, Non-Hodgkin Lymphoma, B-Cell Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Gemcitabine Lenalidomide Loncastuximab tesirine Antimetabolites, Antineoplastic Antimetabolites |
Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Antiviral Agents Anti-Infective Agents Enzyme Inhibitors Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Angiogenesis Inhibitors Angiogenesis Modulating Agents Growth Substances Growth Inhibitors Antineoplastic Agents, Immunological |