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)

Sponsor

ADC Therapeutics S.A. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04970901

Collaborator

(none)

200

Enrollment

Locations

Arms

43.8

Anticipated Duration (Months)

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The primary objective of this study is to characterize the safety and tolerability of loncastuximab tesirine in combination with gemcitabine, lenalidomide, polazutumab vedotin, or umbralisib, and to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) for the combinations.

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

Detailed Description

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 Design

Study Type:

Interventional

Anticipated 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 :

Jun 17, 2022

Anticipated Primary Completion Date :

Feb 12, 2025

Anticipated Study Completion Date :

Feb 10, 2026

Arms and Interventions

Arm	Intervention/Treatment
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: ZYNLONTA ADCT-402 Drug: Gemcitabine Intravenous (IV) infusion
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: ZYNLONTA ADCT-402 Drug: Lenalidomide Orally via capsules
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).	Drug: Loncastuximab Tesirine Intravenous (IV) infusion Other Names: ZYNLONTA ADCT-402 Drug: Polatuzumab Vedotin Intravenous (IV) infusion
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: ZYNLONTA ADCT-402 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: ZYNLONTA ADCT-402 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: ZYNLONTA ADCT-402 Drug: Lenalidomide Orally via capsules
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: ZYNLONTA ADCT-402 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: ZYNLONTA ADCT-402 Drug: Umbralisib Orally via tablets

Outcome Measures

Primary Outcome Measures

Number of Participants Who Experience a Treatment-emergent Adverse Event (TEAE) [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) [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 [Up to approximately 1 year]
Number of Participants Who Experience an Adverse Event (AE) Leading to Dose Interruption [Up to approximately 1 year]
Number of Participants Who Experience an Adverse Event (AE) Leading to Dose Reduction [Up to approximately 1 year]
Number of Participants Who Experience a Clinically Significant Change from Baseline in Safety Laboratory Measurements [Baseline up to approximately 1 year]
Number of Participants Who Experience a Clinically Significant Change from Baseline in Vital Signs [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 [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 [Baseline up to approximately 1 year]

Secondary Outcome Measures

Overall Response Rate (ORR) [Up to approximately 2 years]
Duration of Response (DOR) [Up to approximately 2 years]
Complete Response Rate (CRR) [Up to approximately 2 years]
Progression-Free Survival (PFS) [Up to approximately 2 years]
Relapse-Free Survival (RFS) [Up to approximately 2 years]
Overall Survival (OS) [Up to approximately 2 years]
Average Concentration of Loncastuximab Tesirine [Day 1 to end of treatment (up to approximately 1 year)]
Maximum Concentration (Cmax) of Loncastuximab Tesirine [Day 1 to end of treatment (up to approximately 1 year)]
Time to Maximum Concentration (Tmax) of Loncastuximab Tesirine [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 [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 [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 [Day 1 to end of treatment (up to approximately 1 year)]
Apparent Terminal Elimination Half-Life (Thalf) of Loncastuximab Tesirine [Day 1 to end of treatment (up to approximately 1 year)]
Apparent Clearance (CL) of Loncastuximab Tesirine [Day 1 to end of treatment (up to approximately 1 year)]
Apparent Steady-State Volume of Distribution (Vss) of Loncastuximab Tesirine [Day 1 to end of treatment (up to approximately 1 year)]
Accumulation Index (AI) of Loncastuximab Tesirine [Day 1 to end of treatment (up to approximately 1 year)]
Number of Participants With Anti-Drug Antibody (ADA) Titers to Loncastuximab Tesirine [Day 1 to end of treatment (up to approximately 1 year)]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Memorial Cancer Institute - Memorial Hospital West	Pembroke Pines	Florida	United States	33028
2	The Blood and Marrow Transplant Group of Georgia	Atlanta	Georgia	United States	30342
3	Hollings Cancer Center	Charleston	South Carolina	United States	29425
4	Avera Cancer Institute	Sioux Falls	South Dakota	United States	57105
5	Emily Couric Clinical Cancer Center	Charlottesville	Virginia	United States	22903
6	NEXT Virginia	Fairfax	Virginia	United States	22031
7	Universitair Ziekenhuis Gent	Gent		Belgium	9000
8	Centre Hospitalier Universitaire Universite Catholique de Louvain - Site Godinne	Yvoir		Belgium	B-5530
9	Fakultni nemocnice Ostrava	Ostrava		Czechia	708 52
10	Fakultní Nemocnice Královské Vinohrady	Prague		Czechia	100 34
11	Fakultni nemocnice v Motole	Prague		Czechia	150 06
12	Azienda Socio Sanitaria Territoriale (ASST) degli Spedali Civili di Brescia	Brescia		Italy	25123
13	Istituto Europeo di Oncologia	Milano		Italy	20141
14	Institut Català d'Oncologia - Hospital Duran i Reynals (ICO L'Hospitalet)	Barcelona		Spain	08908
15	Hospital General Universitario Gregorio Marañón	Madrid		Spain	28007
16	Hospital Universitario Ramón y Cajal	Madrid		Spain	28034
17	Complejo Asistencial Universitario de Salamanca - Hospital Clínico	Salamanca		Spain	37007
18	Hospital Universitari i Politècnic La Fe	Valencia		Spain	46026
19	University College London Hospitals NHS Foundation Trust	London		United Kingdom	NW1 2PG
20	Oxford University Hospitals NHS Foundation Trust	Oxford		United Kingdom	OX3 7LE