NCT02875223

A Safety and Efficacy Study of CC-90011 in Participants With Relapsed and/or Refractory Solid Tumors and Non-Hodgkin's Lymphomas

Terminated Phase 1 Results posted Last updated 20 April 2025

What this trial tests

Phase 1 trial testing CC-90011 in Lymphoma, Non-Hodgkin in 75 participants. Terminated before completion.

Timeline

31 August 2016

Primary endpoint
25 March 2024

25 March 2024

Quick facts

Lead sponsor	Celgene
Phase	Phase 1
Status	Terminated
Study type	INTERVENTIONAL
Allocation	non randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	75
Start date	31 August 2016
Primary completion	25 March 2024
Estimated completion	25 March 2024
Sites	15 locations across France, Italy, Japan, United Kingdom, Spain

Drugs / interventions tested

• CC-90011 — full drug profile →
• Rifampicin (Rifampicin) — full drug profile →
• Itraconazole — full drug profile →

Conditions studied

• Lymphoma, Non-Hodgkin — all drugs for Lymphoma, Non-Hodgkin →
• Neoplasms — all drugs for Neoplasms →

Sponsor

Celgene — full company profile →

Who can join

18 and older, any sex, with Lymphoma, Non-Hodgkin or Neoplasms. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Part A - Number of Participants With Dose Limiting Toxicities (DLTs) Primary · Cycle 1 (Each cycle is of 28 days)

Dose-limiting toxicities (DLTs) during dose escalation are defined as follows, occurring within the Cycle 1 (28 days) DLT assessment period, unless clearly unrelated to CC-90011: Any Grade 4 non-hematologic toxicity; any non-hematologic toxicity Grade ≥ 3 except Grade 3 diarrhea, nausea, or vomiting of ≤ 3 days duration, Grade 3 rash resolving to Grade ≤ 2 within 7 days without recurrence, and Grade 3 fatigue resolving to Grade ≤ 2 within 7 days without recurrence. Hematological toxicities include febrile neutropenia, Grade 4 neutropenia \> 7 days, Grade 4 thrombocytopenia \> 7 days, or Grade

Group	Value	95% CI
Part A 1.25 mg	0
Part A 2.5 mg	0
Part A 5 mg	0
Part A 10 mg	0
Part A 20 mg	0
Part A 40 mg	0
Part A 60 mg	1
Part A 80 mg	2
Part A 120 mg	4

Part A - Clinical Benefit Rate (CBR) as Per Confirmed Best Overall Response Based on Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 (RECIST 1.1) Secondary · From first dose (Day 1) till disease progression or death due to any cause (up to 803 days)

The Clinical benefit rate (CBR) is defined as percentage of participants with tumor responses (as assessed by the Investigators) of CR, PR and durable SD (SD of ≥ 4 months duration). Complete response (CR) is defined as complete disappearance of all target lesions with the exception of nodal disease. Partial response (PR) is defined as \\\>=30% decrease under baseline of the sum of diameters of all target measurable lesions. Stable Disease (SD) is concluded when the response does not qualify for CR, PR or Progression. Progression is defined as 20% increase in the sum of diameters of target mea

Group	Value	95% CI
Part A 1.25 mg	0.0	0.0 – 60.2
Part A 2.5 mg	0.0	0.0 – 52.2
Part A 5 mg	16.7	0.4 – 64.1
Part A 10 mg	0.0	0.0 – 60.2
Part A 20 mg	20.0	0.5 – 71.6
Part A 40 mg	50.0	11.8 – 88.2
Part A 60 mg	33.3	4.3 – 77.7
Part A 80 mg	30.0	6.7 – 65.2
Part A 120 mg	0.0	0.0 – 60.2

Part A - Objective Response Rate as Per Confirmed Best Overall Response Based on Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 (RECIST 1.1) Secondary · From first dose (Day 1) untill disease progression or death due to any cause (up to 803 days)

The Objective Response Rate (ORR) is defined as the percentage of participants whose best response is CR or PR. Complete response (CR) is defined as complete disappearance of all target lesions with the exception of nodal disease. Partial response (PR) is defined as \\\>=30% decrease under baseline of the sum of diameters of all target measurable lesions. Progression is defined as 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy) with a minimum absolute increase of 5 mm.

Group	Value	95% CI
Part A 1.25 mg	0.0	0.0 – 60.2
Part A 2.5 mg	0.0	0.0 – 52.2
Part A 5 mg	0.0	0.0 – 45.9
Part A 10 mg	0.0	0.0 – 60.2
Part A 20 mg	0.0	0.0 – 52.2
Part A 40 mg	0.0	0.0 – 45.9
Part A 60 mg	0.0	0.0 – 45.9
Part A 80 mg	10.0	0.3 – 44.5
Part A 120 mg	0.0	0.0 – 60.2

Part A - Duration of Response (DoR) Based on Confirmed Responses Secondary · From first dose (Day 1) until disease progression or death due to any cause (up to 803 days)

Duration of response is measured from the time when criteria for CR/PR are first met (whichever is first recorded) until the first date at which progressive disease is objectively documented. Complete response (CR) is defined as complete disappearance of all target lesions with the exception of nodal disease. Partial response (PR) is defined as \\\>=30% decrease under baseline of the sum of diameters of all target measurable lesions. Progression is defined as 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the s

Group	Value	95% CI
Part A 80 mg	NA	NA – NA

Part A - Progression-Free Survival (PFS) Secondary · From first dose (Day 1) until disease progression or death due to any cause (up to 803 days)

Progression-Free Survival (PFS) is defined as the time from the first dose of CC-90011 to the first occurrence of disease progression or death from any cause based on Kaplan-Meier methodology. Progression is defined as 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy) with a minimum absolute increase of 5 mm.

Group	Value	95% CI
Part A 1.25 mg	96.0	50.0 – 103.0
Part A 2.5 mg	53.0	50.0 – 189.0
Part A 5 mg	107.0	22.0 – NA
Part A 10 mg	51.5	22.0 – 106.0
Part A 20 mg	588.0	50.0 – 588.0
Part A 40 mg	162.0	20.0 – NA
Part A 60 mg	111.5	53.0 – NA
Part A 80 mg	52.0	17.0 – 164.0
Part A 120 mg	107.0	61.0 – 238.0

Part A - Overall Survival (OS) Secondary · From first dose (Day 1) until death due to any cause (up to 803 days)

Overall Survival (OS) is defined as the time from the first dose of study drug to death due to any cause based on Kaplan-Meier methodology.

Group	Value	95% CI
Part A 1.25 mg	315.0	108.0 – 803.0
Part A 2.5 mg	189.0	53.0 – 204.0
Part A 5 mg	611.0	78.0 – NA
Part A 10 mg	322.5	114.0 – 593.0
Part A 20 mg	NA	116.0 – NA
Part A 40 mg	NA	81.0 – NA
Part A 60 mg	NA	153.0 – NA
Part A 80 mg	139.0	27.0 – NA
Part A 120 mg	238.0	185.0 – NA

Part A - Maximum Observed Plasma Concentration (Cmax) of CC-90011 Secondary · Day 1 and Day 22 of Cycle 1 (Each cycle consist of 28 days)

Blood samples were collected to assess Cmax. Prespecified to be reported for Part A only.

Cycle 1 Day 1

Group	Value	95% CI
Part A 1.25 mg	0.4077	± 35.18
Part A 2.5 mg	0.8042	± 46.38
Part A 5 mg	1.520	± 39.99
Part A 10 mg	2.514	± 32.41
Part A 20 mg	4.526	± 75.80
Part A 40 mg	16.28	± 40.03
Part A 60 mg	23.02	± 55.31
Part A 80 mg	23.66	± 37.60
Part A 120 mg	42.03	± 45.99

Cycle Day 22

Group	Value	95% CI
Part A 1.25 mg	0.4181	± 48.30
Part A 2.5 mg	0.7708	± 42.21
Part A 5 mg	1.651	± 45.37
Part A 10 mg	3.886	± 28.94
Part A 20 mg	6.924	± 62.53
Part A 40 mg	10.85	± 29.33
Part A 60 mg	20.43	± 51.67
Part A 80 mg	25.26	± 62.11

Part A - Area Under the Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUCt) of CC-90011 Secondary · Day 1 and Day 22 of Cycle 1 (Each cycle consist of 28 days)

Blood samples were collected to assess AUCt. Prespecified to be reported for Part A only.

Cycle 1 Day 1

Group	Value	95% CI
Part A 1.25 mg	5.806	± 55.98
Part A 2.5 mg	24.47	± 76.85
Part A 5 mg	44.77	± 35.77
Part A 10 mg	103.07	± 42.47
Part A 20 mg	179.48	± 136.69
Part A 40 mg	551.55	± 19.29
Part A 60 mg	704.82	± 60.95
Part A 80 mg	849.47	± 45.94
Part A 120 mg	1736.85	± 25.11

Cycle Day 22

Group	Value	95% CI
Part A 1.25 mg	11.48	± 40.94
Part A 2.5 mg	23.54	± 25.12
Part A 5 mg	45.30	± 46.78
Part A 10 mg	125.53	± 8.738
Part A 20 mg	237.12	± 83.11
Part A 40 mg	337.92	± 30.72
Part A 60 mg	625.53	± 24.73
Part A 80 mg	654.76	± 55.42

Part A - Time to Cmax (Tmax) of CC-90011 Secondary · Day 1 and Day 22 of Cycle 1 (Each cycle consist of 28 days)

Blood samples were collected to assess Tmax. Prespecified to be reported for Part A only.

Cycle 1 Day 1

Group	Value	95% CI
Part A 1.25 mg	2.083	2.050 – 4.000
Part A 2.5 mg	2.017	2.000 – 4.083
Part A 5 mg	4.042	2.000 – 4.133
Part A 10 mg	2.000	1.917 – 2.000
Part A 20 mg	4.183	4.017 – 6.133
Part A 40 mg	4.117	2.000 – 8.067
Part A 60 mg	4.075	4.000 – 6.000
Part A 80 mg	4.042	3.950 – 6.000
Part A 120 mg	3.242	2.083 – 6.000

Cycle Day 22

Group	Value	95% CI
Part A 1.25 mg	2.008	1.950 – 4.067
Part A 2.5 mg	2.992	1.983 – 4.017
Part A 5 mg	3.917	1.983 – 4.067
Part A 10 mg	4.000	3.833 – 4.167
Part A 20 mg	4.567	2.000 – 6.000
Part A 40 mg	4.067	4.000 – 6.000
Part A 60 mg	3.950	1.867 – 6.000
Part A 80 mg	2.083	2.000 – 6.000

Part A - Half-life (t1/2) of CC-90011 Secondary · Day 1 and Day 22 of Cycle 1 (Each cycle consist of 28 days)

Blood samples were collected to assess CL/F. Prespecified to be reported for Part A only.

Cycle 1 Day 1

Group	Value	95% CI
Part A 1.25 mg	34.33	20.93 – 66.63
Part A 2.5 mg	73.07	41.84 – 83.70
Part A 5 mg	79.30	28.86 – 108.39
Part A 10 mg	70.54	51.66 – 94.99
Part A 20 mg	68.35	48.87 – 105.32
Part A 40 mg	59.82	48.34 – 72.33
Part A 60 mg	63.88	50.57 – 90.40
Part A 80 mg	58.52	46.48 – 79.08
Part A 120 mg	67.33	61.17 – 75.06

Cycle Day 22

Group	Value	95% CI
Part A 1.25 mg	77.27	76.35 – 88.38
Part A 2.5 mg	73.25	67.30 – 96.45
Part A 5 mg	53.62	25.83 – 82.82
Part A 10 mg	72.52	62.75 – 73.84
Part A 20 mg	55.76	44.35 – 139.08
Part A 40 mg	71.88	41.58 – 92.17
Part A 60 mg	61.03	50.61 – 81.10
Part A 80 mg	56.03	30.47 – 86.98

Part A - Apparent Clearance (CL/F) of CC-90011 Secondary · Day 1 and Day 22 of Cycle 1 (Each cycle consist of 28 days)

Blood samples were collected to assess CL/F. Prespecified to be reported for Part A only.

Cycle 1 Day 1

Group	Value	95% CI
Part A 2.5 mg	35.61	± NA
Part A 5 mg	95.70	± 20.82
Part A 10 mg	80.08	± 44.68
Part A 20 mg	64.69	± 79.21
Part A 40 mg	63.23	± 23.92
Part A 60 mg	73.37	± 65.85
Part A 80 mg	81.99	± 50.36
Part A 120 mg	57.51	± 27.62

Part A- Volume of Distribution (Vz/F) of CC-90011 Secondary · Day 1 and Day 22 of Cycle 1 (Each cycle consist of 28 days)

Blood samples were collected to assess Vz/F. Prespecified to be reported for Part A only.

Cycle 1 Day 1

Group	Value	95% CI
Part A 2.5 mg	3400.66	± NA
Part A 5 mg	7814.20	± 50.12
Part A 10 mg	8076.70	± 44.02
Part A 20 mg	5734.70	± 64.00
Part A 40 mg	5506.05	± 20.02
Part A 60 mg	7245.99	± 73.93
Part A 80 mg	6984.46	± 37.88
Part A 120 mg	5598.55	± 19.95

Adverse events — posted to ClinicalTrials.gov

Time frame: All cause mortality was collected in Part A (up to 803 days) and Part B (up to 720 days). Adverse Events (AEs) and Serious AEs were collected from first dose (Day 1) and up to 28 days after last dose for participants in Part A (up to approximately 114 weeks) and Part B (up to approximately 256 weeks).. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Part A 1.25 mg

Serious: 2/4 (50%)

Deaths: 4/4

Part A 2.5 mg

Serious: 2/5 (40%)

Deaths: 4/5

Part A 5 mg

Serious: 2/6 (33%)

Deaths: 3/6

Part A 10 mg

Serious: 0/4 (0%)

Deaths: 4/4

Part A 20 mg

Serious: 0/5 (0%)

Deaths: 2/5

Part A 40 mg

Serious: 5/6 (83%)

Deaths: 3/6

Part A 60 mg

Serious: 3/6 (50%)

Deaths: 5/6

Part A 80 mg

Serious: 6/10 (60%)

Deaths: 7/10

Part A 120 mg

Serious: 3/4 (75%)

Deaths: 3/4

Part B 60 mg

Serious: 7/25 (28%)

Deaths: 14/25

Serious adverse events (40 terms)

Reaction	System	Part A 1.25 mg	Part A 2.5 mg	Part A 5 mg	Part A 10 mg	Part A 20 mg	Part A 40 mg	Part A 60 mg	Part A 80 mg	Part A 120 mg	Part B 60 mg
Thrombocytopenia	Blood and lymphatic system disorders	—	—	—	—	—	—	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—	—	—	—	—	—	—
Neutropenia	Blood and lymphatic system disorders	—	—	—	—	—	—	—	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—
Colitis	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—
Duodenal obstruction	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—
Haematemesis	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—
Oesophageal ulcer	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—
Small intestinal obstruction	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—
Chest pain	General disorders	—	—	—	—	—	—	—	—	—	—
Fatigue	General disorders	—	—	—	—	—	—	—	—	—	—
General physical health deterioration	General disorders	—	—	—	—	—	—	—	—	—	—
Pyrexia	General disorders	—	—	—	—	—	—	—	—	—	—
Cholecystitis	Hepatobiliary disorders	—	—	—	—	—	—	—	—	—	—
Hepatic haemorrhage	Hepatobiliary disorders	—	—	—	—	—	—	—	—	—	—
Hepatic pain	Hepatobiliary disorders	—	—	—	—	—	—	—	—	—	—
Portal vein thrombosis	Hepatobiliary disorders	—	—	—	—	—	—	—	—	—	—
Biliary tract infection	Infections and infestations	—	—	—	—	—	—	—	—	—	—
Cystitis	Infections and infestations	—	—	—	—	—	—	—	—	—	—
Upper respiratory tract infection	Infections and infestations	—	—	—	—	—	—	—	—	—	—
Wound infection	Infections and infestations	—	—	—	—	—	—	—	—	—	—
Oxygen saturation decreased	Investigations	—	—	—	—	—	—	—	—	—	—
Weight decreased	Investigations	—	—	—	—	—	—	—	—	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—	—	—	—	—	—	—	—	—

Other adverse events (161 terms — click to expand)

Reaction	System	Part A 1.25 mg	Part A 2.5 mg	Part A 5 mg	Part A 10 mg	Part A 20 mg	Part A 40 mg	Part A 60 mg	Part A 80 mg	Part A 120 mg	Part B 60 mg
Thrombocytopenia	Blood and lymphatic system disorders	—	—	—	—	—	—	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—	—	—	—	—	—	—
Neutropenia	Blood and lymphatic system disorders	—	—	—	—	—	—	—	—	—	—
Asthenia	General disorders	—	—	—	—	—	—	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—
Leukopenia	Blood and lymphatic system disorders	—	—	—	—	—	—	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—
Lipase increased	Investigations	—	—	—	—	—	—	—	—	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—	—	—	—	—	—	—	—	—
Dysgeusia	Nervous system disorders	—	—	—	—	—	—	—	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—	—	—	—
Fatigue	General disorders	—	—	—	—	—	—	—	—	—	—
Aspartate aminotransferase increased	Investigations	—	—	—	—	—	—	—	—	—	—
Hypokalaemia	Metabolism and nutrition disorders	—	—	—	—	—	—	—	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—	—	—	—	—
Bone pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—	—	—	—	—
Dizziness	Nervous system disorders	—	—	—	—	—	—	—	—	—	—
Insomnia	Psychiatric disorders	—	—	—	—	—	—	—	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—	—	—	—
Epistaxis	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—	—	—	—
Excessive cerumen production	Ear and labyrinth disorders	—	—	—	—	—	—	—	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—
Dyspepsia	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—
Gastrooesophageal reflux disease	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—
Stomatitis	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—
Pyrexia	General disorders	—	—	—	—	—	—	—	—	—	—
Bronchitis	Infections and infestations	—	—	—	—	—	—	—	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—	—	—	—	—	—	—	—
Amylase increased	Investigations	—	—	—	—	—	—	—	—	—	—
Blood alkaline phosphatase increased	Investigations	—	—	—	—	—	—	—	—	—	—
Hypercalcaemia	Metabolism and nutrition disorders	—	—	—	—	—	—	—	—	—	—
Musculoskeletal pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—	—	—	—	—
Neck pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—	—	—	—	—
Tumour pain	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—	—	—	—	—	—	—
Headache	Nervous system disorders	—	—	—	—	—	—	—	—	—	—
Hypoaesthesia	Nervous system disorders	—	—	—	—	—	—	—	—	—	—
Peripheral sensory neuropathy	Nervous system disorders	—	—	—	—	—	—	—	—	—	—

Most-reported serious reactions: Thrombocytopenia, Anaemia, Neutropenia, Abdominal pain, Colitis, Constipation, Duodenal obstruction, Haematemesis.

Data from ClinicalTrials.gov NCT02875223 adverse events section.

Sponsor's own description

Study CC-90011-ST-001 is an open-label, Phase 1, dose escalation and expansion, First-In-Human (FIH) clinical study of CC-90011 in subjects with advanced unresectable solid tumors (enriched for grade 2 NENs, grade 2 NETs and NECs) and R/R NHL (MZL, including extranodal MZL \[EMZL\], splenic MZL \[SMZL\], nodal MZL \[NMZL\], and histologic transformation of MZL). The dose escalation part (Part A) of the study will explore escalating oral doses of CC-90011 to estimate the maximum tolerated dose (MTD) of CC-90011. The expansion part (Part B) will further evaluate the safety and efficacy of CC-90011 administered at or below the MTD in 3 selected expansion cohorts of approximately 10-20 evaluable subjects each, in order to further define the RP2D.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Tumor biomarkers for diagnosis, prognosis and targeted therapy.
   Zhou Y, Tao L, Qiu J, Xu J, et al · · 2024 · cited 379× · PMID 38763973 · DOI 10.1038/s41392-024-01823-2
2. LSD1/KDM1A inhibitors in clinical trials: advances and prospects.
   Fang Y, Liao G, Yu B, Yu B. · · 2019 · cited 316× · PMID 31801559 · DOI 10.1186/s13045-019-0811-9
3. Targeting epigenetic regulators to overcome drug resistance in cancers.
   Wang N, Ma T, Yu B, Yu B. · · 2023 · cited 213× · PMID 36797239 · DOI 10.1038/s41392-023-01341-7
4. Epigenetics-targeted drugs: current paradigms and future challenges.
   Dai W, Qiao X, Fang Y, Guo R, et al · · 2024 · cited 131× · PMID 39592582 · DOI 10.1038/s41392-024-02039-0
5. Methylation across the central dogma in health and diseases: new therapeutic strategies.
   Liu R, Zhao E, Yu H, Yuan C, et al · · 2023 · cited 79× · PMID 37620312 · DOI 10.1038/s41392-023-01528-y
6. LSD1 inhibitors for cancer treatment: Focus on multi-target agents and compounds in clinical trials.
   Noce B, Di Bello E, Fioravanti R, Mai A. · · 2023 · cited 78× · PMID 36817147 · DOI 10.3389/fphar.2023.1120911
7. Clinical activity of CC-90011, an oral, potent, and reversible LSD1 inhibitor, in advanced malignancies.
   Hollebecque A, Salvagni S, Plummer R, Niccoli P, et al · · 2022 · cited 39× · PMID 35737639 · DOI 10.1002/cncr.34366
8. Pharmacological targeting of the cancer epigenome.
   Mabe NW, Perry JA, Malone CF, Stegmaier K. · · 2024 · cited 36× · PMID 38937652 · DOI 10.1038/s43018-024-00777-2