Abstract 91P
Background
Early phase clinical trials have evolved markedly over the last decade. The urgent need for drug development for cancer patients, together with the greater complexity of new therapies, have led to the increasing importance of expansion cohorts (ECs) within phase 1 trial design.
Methods
We conducted a systematic review of MEDLINE and EMBASE, focusing on oncology phase I trials with ECs involving adult participants published from 2019 to 2023. The objective was to assess the characteristics, purpose and outcomes of ECs. Two reviewers performed eligibility assessment before data extraction was completed. Descriptive analysis was made, and statistical associations were evaluated.
Results
479 published phase 1 trials with ECs were analysed. The objective of the ECs was clearly stated in 55.7% of studies (42.8% safety, 9.2% dose refinement, 14.4% pharmacokinetics, 12.3% pharmacodynamics and 43.2% efficacy) whilst in 44.3% of studies it was not clearly defined. The mean Overall Response Rate (ORR) and Disease Control Rate (DCR) for studies recruiting solid tumour patients was 19.1% and 56.2% versus 40.6% and 64.0% for haematological trials. Sample size did not correlate with the ORR (Pearson's rho = 0.027; p = 0.583) or DCR (Pearson’s rho = -0.006; p = 0.910). Combination trials had higher mean ORR (27.7% vs 19.8% p<0.001) and DCR (61.1% vs 54.4% p=0.004) than monotherapy trials. ADC trials showed the highest mean ORR (32.1%) and DCR (70.6%) among the classes of drugs. Only 5.2% trials changed the Recommended phase 2 Dose after the EC. 59.1% of the reviewed studies progressed to later-stage trials registered in clinicaltrials.gov. Trials with further development to phase 2/3 had higher mean ORR (26.8% vs 18.8% p<0.001), but not DCR (58.9% vs 55.5%, p=0.150). Table: 91P
Phase I clinical trials’ characteristics
| Characteristics | Trials with expansion cohorts (N=479) | ||
| No. | % | ||
| Patients enrolled | Mean | 42 | |
| Range | 1-292 | ||
| Sponsor | Academic | 77 | 16.1 |
| Industry | 402 | 83.9 | |
| Center | Unicenter | 53 | 11.1 |
| Multicenter | 426 | 88.9 | |
| Continent | North America | 310 | 64.7 |
| Asia | 188 | 39.2 | |
| Europe | 177 | 37 | |
| Oceania | 38 | 7.9 | |
| Combination | Monotherapy | 248 | 51.8 |
| Combination therapy | 231 | 48.2 | |
| Class of agent in monotherapy | Chemotherapy / Antibody-Drug Conjugates (ADC) | 41 | 16.5 |
| Immunotherapy | 43 | 17.3 | |
| Targeted therapy | 142 | 57.3 | |
| Others | 22 | 8.9 | |
| Dose finding strategy | Rule based | 383 | 80 |
| Model based | 52 | 10.9 | |
| Not stated | 44 | 9.2 | |
| Statistical justification of expansion cohort | Yes | 117 | 24.4 |
| No | 362 | 75.6 | |
Conclusions
Characteristics and outcomes of modern ECs within phase 1 clinical trials are heterogeneous. To support recruitment of the increased patient numbers clear descriptions of EC objectives are critical.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
X. Hu: Financial Interests, Personal, Full or part-time Employment: The Institute of Cancer Research. C. Yap: Financial Interests, Personal, Advisory Board, Statistical Consultant: Faron Pharmaceutical; Financial Interests, Personal, Invited Speaker, Speaker at a Training Workshop: Bayer; Financial Interests, Institutional, Research Grant: AstraZeneca, Celgene, Novartis; Financial Interests, Personal and Institutional, Research Grant: Faron Pharmaceuticals. L. Carter: Financial Interests, Personal, Other, Consultancy: Bicycle Therapeutics, Boehringer Ingelheim, Athenex; Financial Interests, Personal, Full or part-time Employment, Medical Advisor: Cancer research UK Centre for Drug Development; Financial Interests, Institutional, Invited Speaker: Boehringer Ingelheim, Bicycle Therapeutics, Cellcentric, Eli Lily, Athenex, Lupin Limited, Repare Therapeutics, Cytomx therapeutics, EMD Serono/Merck KGaA, Sierra Oncology, Nurix Therapeutics, ADC Therapeutics, Takeda; Financial Interests, Institutional, Invited Speaker, Funding for delivering commercial trial activity: Genmab. All other authors have declared no conflicts of interest.