ADC Therapeutics Announces Voluntary Pause of Enrollment in the Phase 2 LOTIS-9 Clinical Trial of ZYNLONTA® (loncastuximab tesirine-lpyl) and Rituximab in Unfit or Frail Previously Untreated DLBCL Patients

Rhea-AI Summary

ADC Therapeutics has announced a voluntary pause in the enrollment of new patients in the Phase 2 LOTIS-9 clinical trial evaluating ZYNLONTA and rituximab in unfit or frail patients with previously untreated diffuse large B-cell lymphoma. The pause was initiated due to potentially excessive respiratory-related events, including seven Grade 5 fatal events and five Grade 3 or Grade 4 respiratory-related TEAEs. The cause of these events is under investigation. All patients with fatal events had significant underlying respiratory and/or cardiac co-morbidities and were over 80 years old.

LAUSANNE, Switzerland, July 11, 2023 (GLOBE NEWSWIRE) -- ADC Therapeutics SA (NYSE: ADCT) today announced a voluntary pause in the enrollment of new patients in the Phase 2 LOTIS-9 clinical trial (ClinicalTrials.gov Identifier: NCT05144009) evaluating ZYNLONTA^® (loncastuximab tesirine-lpyl) and rituximab (Lonca-R) in unfit or frail patients with previously untreated diffuse large B-cell lymphoma (DLBCL).

The voluntary action was taken by the Company after a recent review of aggregate data of the 40 patients enrolled in the trial and consultation with the Data Monitoring Committee (DMC) which signaled potentially excessive respiratory-related events. These respiratory-related treatment-emergent adverse events (TEAEs) included seven Grade 5 fatal events and five Grade 3 or Grade 4 respiratory-related TEAEs. As per investigator assessment, eleven of the twelve events (including six of the seven Grade 5 fatal events) were individually assessed as unlikely or unrelated to study drug. Four out of the five Grade 3 or Grade 4 events have since resolved and the patients have completed treatment per protocol. The cause of these events remains under further investigation.

All patients with fatal events had one or more significant active underlying respiratory and/or cardiac co-morbidities including severe chronic obstructive pulmonary disease (COPD), pulmonary edema, chronic bronchiectasis, idiopathic pulmonary fibrosis and recent COVID-19 infection and all were greater than or equal to 80 years of age. The mean age was 82.7 years and the mean number of days from the last dose to death was 51 days, with a range of 19 to 86 days. It is important to note that all twelve of the patients with Grade 3-5 TEAEs in the LOTIS-9 study would have been excluded from the LOTIS-5 trial.

The Company’s decision to pause enrollment enables time to evaluate data around the TEAEs and determine next steps. The Company has notified all study investigators and regulatory authorities including the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) of the Company’s decision to pause enrollment. The Company does not expect to report additional data from the trial by the end of the year.

“Our top priority is the safety of every patient who participates in our clinical trials,” said Ameet Mallik, Chief Executive Officer of ADC Therapeutics. “Given the aggregate of the respiratory-related events seen in the trial, we implemented a voluntary pause of enrollment to allow for a thorough investigation of the data set. This trial includes a very difficult-to-treat patient population with limited treatment options, and we will provide an update on next steps when available.”

LOTIS-9 Baseline Characteristics, Safety and Efficacy (as of May 10, 2023 data cutoff)

The tables below illustrate preliminary data from the LOTIS-9 clinical trial with a data cut-off date of May 10, 2023. These data are reflective of the 30 patients who were enrolled by that point; since this time an additional 10 patients have enrolled and received treatment as part of the study.

Table 1 – Baseline Characteristics

Variable	Cohort A (Unfit)	Cohort B (Frail or cardiac comorbidities)	Total
	(N=13)	(N=17)	(N=30)
Age (years)
n	13	17	30
Mean	83.4	82.2	82.7
std	2.69	6.26	5
Median	83	82	82
Min, Max	80, 89	72, 92	72, 92
Sex, [n(%)]
Female	3 (23.1)	7 (41.2)	10 (33.3)
Male	10 (76.9)	10 (58.8)	20 (66.7)
Stage of Disease at Study Entry, n (%)
Stage I	1 (7.7)	1 (5.9)	2 (6.7)
Stage II	3 (23.1)	4 (23.5)	7 (23.3)
Stage III	6 (46.2)	7 (41.2)	13 (43.3)
Stage IV	3 (23.1)	5 (29.4)	8 (26.7)

Table 2 – Treatment-Emergent Adverse Events with Fatal Outcome

	Cohort A (Unfit)	Cohort B (Frail or cardiac comorbidities)	Total
	(N=13)	(N=17)	(N=30)
Patients with any fatal TEAE	3 (23.1)	3 (17.6)	6 (20.0)
Infections and infestations	0	1 (5.9)	1 (3.3)
Pneumonia	0	1 (5.9)	1 (3.3)
Respiratory, thoracic and mediastinal disorders	3 (23.1)	2 (11.8)	5 (16.7)
Acute respiratory failure	1 (7.7)	0	1 (3.3)
Chronic obstructive pulmonary disease	0	1 (5.9)	1 (3.3)
Dyspnoea	1 (7.7)	0	1 (3.3)
Hypoxia	0	1 (5.9)	1 (3.3)
Respiratory failure	1 (7.7)	0	1 (3.3)

Since the data cut-off date of May 10, 2023, there has been one additional Grade 5 event for a total of seven Grade 5 events. Two out of seven patients died within 30 days from the last doses of study medication, the remaining 5 patients died more than 30 days after the last dose of study drug ranging from 41 to 86 days. Adverse events are coded using MedDRA version 24.1 and graded using CTCAE v5.0. Only treatment-emergent adverse events are summarized. For each system organ class and preferred term, patients are included only once.

Table 3 – Treatment-Emergent Grade 3 or 4 Adverse Events – Cardiac, Infections / Infestations, Respiratory, Thoracic and Mediastinal Disorders and Others ≥5% Total Occurrence*

	Cohort A (Unfit)	Cohort B (Frail or cardiac comorbidities)	Total
	(N=13)	(N=17)	(N=30)
Patients with any grade >=3 TEAE	2 (15.4)	7 (41.2)	9 (30.0)
Cardiac disorders	1 (7.7)	1 (5.9)	2 (6.7)
Infections and infestations	0	2 (11.8)	2 (6.7)
Pneumonia	0	2 (11.8)	2 (6.7)
COVID-19 pneumonia	0	1 (5.9)	1 (3.3)
Influenza	0	1 (5.9)	1 (3.3)
Sepsis	0	1 (5.9)	1 (3.3)
Respiratory, thoracic and mediastinal disorders	1 (7.7)	3 (17.6)	4 (13.3)
Acute respiratory failure	1 (7.7)	1 (5.9)	2 (6.7)
Pleural effusion	1 (7.7)	1 (5.9)	2 (6.7)
Dyspnoea	1 (7.7)	0	1 (3.3)
Respiratory distress	0	1 (5.9)	1 (3.3)
Vascular disorders	1 (7.7)	1 (5.9)	2 (6.7)

Since the data cut-off date of May 10, 2023, there has been one additional Grade 3 or 4 cardiac event, one additional Grade 3 or 4 infection, and one additional Grade 3 or 4 respiratory event.

*Numbers represent distinct TEAEs; patients may have experienced more than one event

Table 4 – Overall Response Rate as Determined by the Investigator

	Cohort A (Unfit)	Cohort B (Frail or cardiac comorbidities)	Total
	(N=10)	(N=7)	(N=17)
Best Overall Response
Complete response	5 (50.0)	5 (71.4)	10 (58.8)
Partial response	5 (50.0)	1 (14.3)	6 (35.3)
Stable disease	0	1 (14.3)	1 (5.9)
Not evaluable	0	0	0
Progressive disease	0	0	0
ORR (CR+PR), n (%)	10 (100)	6 (85.7)	16 (94.1)
95% CI for ORR	(69.2, 100)	(42.1, 99.6)	(71.3, 99.9)
95% CI for CR	(18.7, 81.3)	(29.0, 96.3)	(32.9, 81.6)

Best overall response (BOR) by investigator. Based on efficacy population, i.e., patients with baseline and at least one post-baseline disease assessment.
ORR=Overall Response Rate. CI=Confidence Interval.

About ZYNLONTA^® (loncastuximab tesirine-lpyl)

The U.S. Food and Drug Administration (FDA) and the European Medicines Agency have approved ZYNLONTA (loncastuximab tesirine-lpyl) for the treatment of adult patients with relapsed or refractory (r/r) large B-cell lymphoma after two or more lines of systemic therapy, including DLBCL not otherwise specified, DLBCL arising from low-grade lymphoma and also high-grade B-cell lymphoma. The trial included a broad spectrum of heavily pre-treated patients (median three prior lines of therapy) with difficult-to-treat disease, including patients who did not respond to first-line therapy, patients refractory to all prior lines of therapy, patients with double/triple hit genetics and patients who had stem cell transplant and CAR-T therapy prior to their treatment with ZYNLONTA. This indication is approved by the FDA under accelerated approval and in the European Union under conditional approval based on overall response rate and continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. Please see full prescribing information including important safety information about ZYNLONTA at www.ZYNLONTA.com.

About ADC Therapeutics

ADC Therapeutics (NYSE: ADCT) is a commercial-stage global leader and pioneer in the field of antibody drug conjugates (ADCs). The Company is advancing its proprietary ADC technology to transform the treatment paradigm for patients with hematologic malignancies and solid tumors.

ADC Therapeutics’ CD19-directed ADC ZYNLONTA (loncastuximab tesirine-lpyl) received accelerated approval by the FDA and conditional approval from the European Commission for the treatment of relapsed or refractory diffuse large B-cell lymphoma after two or more lines of systemic therapy. ZYNLONTA is also in development in combination with other agents and in earlier lines of therapy. In addition to ZYNLONTA, ADC Therapeutics has multiple ADCs in ongoing clinical and preclinical development.

ADC Therapeutics is based in Lausanne (Biopôle), Switzerland and has operations in London, the San Francisco Bay Area and New Jersey. For more information, please visit https://www.adctherapeutics.com/ and follow the company on Twitter and LinkedIn.

ZYNLONTA^® is a registered trademark of ADC Therapeutics SA.

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, including statements concerning the investigation of the causes of the pulmonary adverse events, anticipated communications and interactions with regulatory authorities and any actions taken by regulatory authorities or us relating to next steps for our LOTIS-9 or other clinical trials which could include protocol modifications, clinical suspensions or other actions; and statements relating to the development of products and product candidates, and the timing, conduct and results of clinical trials. In some cases you can identify forward-looking statements by terminology such as “may”, “will”, “should”, “would”, “expect”, “intend”, “plan”, “anticipate”, “believe”, “estimate”, “predict”, “potential”, “seem”, “seek”, “future”, “continue”, or “appear” or the negative of these terms or similar expressions, although not all forward-looking statements contain these identifying words. Forward-looking statements are subject to certain risks and uncertainties that can cause actual results to differ materially from those described. Factors that may cause such differences include, but are not limited to: the nature, frequency and severity of adverse events; the ability to complete clinical trials on expected timelines, if at all; the outcome of clinical trials or the sufficiency of results from such clinical trials; the timing and results of the Company’s or its partners’ research projects or clinical trials including LOTIS 5, 7 and 9, ADCT 901, 601 and 602; and the timing and outcome of regulatory submissions and actions by the FDA or other regulatory agencies with respect to the Company’s products or product candidates. Additional information concerning these and other factors that may cause actual results to differ materially from those anticipated in the forward-looking statements is contained in the “Risk Factors” section of the Company's Annual Report on Form 20-F and in the Company's other periodic reports and filings with the Securities and Exchange Commission. The Company cautions investors not to place undue reliance on the forward-looking statements contained in this document. The Company undertakes no obligation to revise or update these forward-looking statements to reflect events or circumstances after the date of this press release, except as required by law.

CONTACTS:

Investors
Eugenia Litz
ADC Therapeutics
Eugenia.Litz@adctherapeutics.com
+44 7879 627205
+1 908-723-2350

Media
Nicole Riley
ADC Therapeutics
Nicole.Riley@adctherapeutics.com
+1 862-926-9040

FAQ

What is the reason for the voluntary pause in the LOTIS-9 clinical trial?

The pause was initiated due to potentially excessive respiratory-related events observed in the trial.

What were the respiratory-related adverse events observed in the trial?

The trial reported seven Grade 5 fatal events and five Grade 3 or Grade 4 respiratory-related TEAEs.

What is the age range of the patients who experienced fatal events?

All patients with fatal events were over 80 years old.

What underlying co-morbidities did the patients with fatal events have?

The patients had significant underlying respiratory and/or cardiac co-morbidities, including severe COPD, pulmonary edema, chronic bronchiectasis, idiopathic pulmonary fibrosis, and recent COVID-19 infection.

Has the cause of these events been determined?

The cause of these events is currently under investigation.