A dose-escalation and dose-expansion study of ADCT-901 in patients with solid tumours
Research type
Research Study
Full title
A Phase 1, Open-Label, Dose-Escalation and Dose-Expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Antitumor Activity of ADCT-901 as Monotherapy in Patients with Selected Advanced Solid Tumors
IRAS ID
1005842
Contact name
Sabine Soldan
Contact email
Sponsor organisation
ADC Therapeutics SA
Eudract number
2021-002292-19
Clinicaltrials.gov Identifier
Research summary
This is a Phase 1, multi-centre, open-label study with two parts consisting of a dose-escalation and a dose expansion part; it will enroll approximately 76 adult participants equal to or over 18 years old. Anti-tumor activity of ADCT-901 has been observed in preclinical studies. This is the first study in which ADCT-901 is being given to humans. The purpose of this study is to understand the best and safe dose level of ADCT-901 to treat participants with advanced malignancies. ADCT-901 is an antibody-drug conjugate (ADC), a type of medicine that combines an antibody (a protein that binds to specific substances in the body) with a chemotherapy drug that can kill cells. The antibody part helps direct the chemotherapy to cancer cells, and kill them. The study will include a screening period, a treatment period and a follow-up period for up to 1 year after the end of treatment. Participants will receive treatment in cycles of 3 weeks as long as needed and/or tolerated. In the dose escalation part, the first three patients will start at a low dose. Each new dose is thereafter increased after at least 3 patients have been dosed with no severe side effects. This dose escalation continues until a dose is identified as the dose to be used in the expansion part. ADCT-901 will be given as an intravenous (IV) infusion over 30 minutes on Day 1 of each cycle. The response to the treatment will be assessed by radiographic tumour assessments and tumour biomarkers. A Dose Escalation Steering Committee (DESC) will be responsible for safety monitoring and overall supervision of the study. The following study procedures will be performed: (a) physical examinations (b) ECGs (c) blood tests, (d) urine tests (e) tumor scans (f) tumour tissue collection (g) IV Infusion (h) questionnaires.
Summary of Research
The study was performed at 13 sites in 3 countries: the USA (7 sites), Spain (4 sites), and United-Kingdom (2 sites). Twenty-two (22) patients were enrolled at sites in the USA, 7 at sites in Spain and 2 patients were enrolled at sites in United Kingdom. Of the 30 patients enrolled, 17 (56.7%) were female and 13 (43.3%) were male. The majority were white (26 patients; 86.7%). The patient ages ranged from 41 years (minimum) to 80 years (maximum), with 16 patients (53.3%) aged less than 65 years, 11 patients (36.7%) aged 65 years to less than 75 years, and 3 patients (10%) aged 75 years or older.
In Part 1, 26 patients received ADCT-901, every 21 days at either the dose of 15 micrograms per kilogram of body weight (equivalent to 1.1 mg), 30 micrograms per kilogram of body weight (equivalent to 2.3 mg), 4.5 mg, 6.8 mg or 9 mg. In Part 2 of the study, 4 patients received ADCT-901, at the dose of 9 mg for the first dose, and then 4.5 mg every 28 days. Due to the side effects related to ADCT-901 observed in Part 1, it was decided to increase the duration of each cycle from 21 days to 28 days.
Of the patients enrolled in the study, 23 patients (76.7%) stopped ADCT-901 treatment because their cancer become worse, 5 patients (16.7%) decided to stop treatment, and 1 patient (3.3%) stopped ADCT-901 due to side effects.
Of the 29 patients who received ADCT-901 and had at least one scan, 1 patient (3.4%) had at least one scan showing their cancer had responded to ADCT-901 (partial response). Ten patients (34.5%) had their cancer stable. Seventeen patients (58.6%) had disease progression. One patient who received ADCT-901 did not have a scan and was considered not evaluable for the activity.
Some of the original research questions (such as how long patients lived for after ADCT-901 treatment) could not be fully addressed because the trial was stopped early and patients were not followed for sufficient time.
The most commonly reported side effects in this study (which were seen in at least 20% of patients) are shown below. It is important to consider that these side effects were not necessarily caused by the treatment with ADCT-901. Some may have been caused or worsened by the patients’ underlying cancer or other health problems, especially considering the older age and ongoing medical problems the patients already had when they joined the study.
• Tiredness (“fatigue”): 14 patients (46.7%)
• Nausea: 12 patients (40.0%)
• Abdominal pain: 9 patients (30.0%)
• Anaemia (decrease of red blood cells): 8 patients (26.7%)
• Decreased appetite: 8 patients (26.7%)
• Fluid buildup in the hands/arms and/or feet/legs (“Oedema peripheral”): 7 patients (23.3%)
• Distended abdomen (Abdominal distension): 6 patients (20.0%)
• Inflammation of the mouth (“stomatitis”): 6 patients (20.0%)Twelve (12) patients (40.0%) who received ADCT-901 reported a serious medical problem (for example, a problem for which they were admitted to hospital). The most common serious medical problems were disorders of the gastrointestinal tract, disorders of the liver, and infections, in 3 or 4 patients for each disorder.
Fourteen patients (46.7%) who received ADCT-901 died during the study. Thirteen deaths were due to the progression of cancer. The remaining death was related to multiple organ dysfunction syndrome considered not related to ADCT-901 by the Study doctor.
In Part 1, at the dose level of 9 mg every 21 days, one patient had a side effect which was considered a limitation for increasing the dose further: this was a side effect of fatigue that prevented the patient from receiving a second dose of ADCT-901 on time and delayed further treatment by more than two weeks. For this reason, it was decided to not test dose levels above 9 mg.
Twenty-five patients (83.3%) had side effects considered by Study doctors as related to ADCT-901. Fourteen patients (46.7%) had moderate side effects related to ADCT-901 and 6 patients (20.0%) had severe ones. These types of side effects were mainly fatigue and gastrointestinal disorders (nausea and inflammation of the mouth).
Six patients (20.0%) had side effects which induced a delay in ADCT-901 administration (5 patients, 16.7%) or an interruption during the administration of the drug (1 patient, 3.3%).
In conclusion, the main side effects of ADCT-901 were fatigue and gastrointestinal side effects (especially inflammation of the mouth). Certain side effects obliged patients to delay ADCT-901 administration.
ADCT-901-101 did not show significant activity in advanced solid tumor cancers that express the protein KAAG1, with only 1 patient out of the 30 patients treated showing a response.
Due to the lack of efficacy, the Sponsor decided to stop the study early.
At this time, there is no plan for further development of ADCT-901.Summary of Results
https://euclinicaltrials.eu/search-for-clinical-trials/?lang=en&EUCT=2022-500115-39-00REC name
East of England - Cambridge Central Research Ethics Committee
REC reference
22/EE/0246
Date of REC Opinion
21 Nov 2022
REC opinion
Further Information Favourable Opinion