Newly-diagnosed Pediatric T-cell ALL Protocol

Phase 2

Not yet recruiting

• Conditions: Acute Lymphoblastic Leukemia; Childhood Leukemia, Acute Lymphoblastic; T Cell Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma
• Interventions: Drug: Venetoclax; Drug: Dasatinib; Drug: homoharringtonine

• Registration Number: NCT06855810
• Lead Sponsor: Institute of Hematology & Blood Diseases Hospital, China

Brief Summary

This is a prospective, multicenter study conducted within the Chinese Children's Cancer Group (CCCG). The study aims to evaluate whether the addition of three novel agents, dasatinib, venetoclax and homoharringtonine, can improve the minimal residual disease (MRD)-negative remission rate, enhance event-free survival (EFS), and reduce the cumulative incidence of relapse (CIR) in pediatric patients with newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL).

Detailed Description

The CCCG-T-ALL-2025 protocol will be modified as following based on the above analysis of the CCCG-ALL-2020 protocol.

1. All T-ALL patients will receive 8 mg/m2/day dexamethasone in induction therapy.

2. All non-ETP T-ALL patients will receive dasatinib after initial window phase in induction therapy.

3. non-ETP T-ALL patients with MRD ≥ 0.01% on day 46 will be stratified and randomized to receive different doses of homoharringtonine during early intensification.

4. For all ETP/near-ETP T-ALL patients, venetoclax will replace daunorubicin in induction therapy.

5. For all ETP/near-ETP T-ALL patients, venetoclax will replace daunorubicin in interim therapy 2 and 4.

6. CAT will replace CAT+ during early intensification, and will be administrated to all ETP/near-ETP patients, as well as non-ETP patients with MRD\< 0.01% on day 46.

2.11.7 In maintenance therapy 2, the CTX+Ara-C treatment cycles are reduced to 5, in order to minimize the impact of alkylating agents on fertility.

2.11.8 Add drug sensitivity testing for T-ALL.

Study Timeline

• Status Verified: 2025-02
• Study First Submitted: 2025-02-04
• Study First Submitted QC: 2025-02-25
• Study Start: 2025-03
• Study First Posted: 2025-03-04
• Last Update Submitted: 2025-03-11
• Last Update Posted: 2025-03-14
• Primary Completion: 2030-06
• Study Completion: 2031-06

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 610

Inclusion Criteria

1. Age older than 1 month to younger than 18 years.
2. Diagnosis of acute lymphoblastic leukemia by bone marrow morphology.
3. Diagnosis of T-ALL by immunophenotyping.

Exclusion Criteria

1. B-ALL
2. AML
3. Acute leukemias of ambiguous lineage diagnosed according to WHO or EGIL criteria.
4. ALL evolved from chronic myeloid leukemia (CML).
5. Down's syndrome, or major congenital or hereditary disease with organ dysfunction
6. Secondary leukemia
7. Known underlying congenital immunodeficiency or metabolic disease
8. Congenital heart disease with cardiac insufficiency.
9. Treated with glucocorticoids for ≥14 days, or ABL kinase inhibitors for > 7 days within one month before enrollment, or any chemotherapy or radiotherapy within 3 months before enrollment (except for emergency radiotherapy to relieve airway compression)
10. Any significant comorbidities or psychiatric disorders that may impact patient safety, compliance, informed consent, study participation, follow-up, or the interpretation of study results. In such cases, all participating sites must report directly to the PI to determine whether the patient meets exclusion criteria.
11. Severe malnutrition, active infections, heart failure, or chemotherapy intolerance.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
(near)ETP-ALL	Venetoclax	All T-ALL patients will receive 8 mg/m2/day dexamethasone in induction therapy. For all ETP/near-ETP T-ALL patients, venetoclax will replace daunorubicin in induction therapy. CAT will replace CAT+ during early intensification. Venetoclax will replace daunorubicin in interim therapy 2 and 4. In maintenance therapy 2, the CTX+Ara-C treatment cycles are reduced to 5, in order to minimize the impact of alkylating agents on fertility.
nonETP-TALL-Das Group	Dasatinib	All T-ALL patients will receive 8 mg/m2/day dexamethasone in induction therapy. All non-ETP T-ALL patients will receive dasatinib after initial window phase in induction therapy. For non-ETP T-ALL patients with MRD \<0.01% on day 46, CAT will replace CAT+ during early intensification, and patients will be continuously subjected to dasatinib combined with chemotherapy during early intensification, interim tharapy, reinduction therapy and maintenance therapy. In maintenance therapy 2, the CTX+Ara-C treatment cycles are reduced to 5, in order to minimize the impact of alkylating agents on fertility.
nonETP-TALL-HHT Group	homoharringtonine	All T-ALL patients will receive 8 mg/m2/day dexamethasone in induction therapy. All non-ETP T-ALL patients will receive dasatinib after initial window phase in induction therapy. For non-ETP T-ALL patients with MRD ≥0.01% on day 46，CAT+ will be replaced with randomized doses of homoharringtonine (HHT) during early intensification, and HHT will be administrated during reinduction therapy. In maintenance therapy 2, the CTX+Ara-C treatment cycles are reduced to 5, in order to minimize the impact of alkylating agents on fertility.

Primary Outcome Measures

Name	Time	Method
End-of-induction(EOI) measurable residual diseases (MRD)-negativity rate in patients with non-ETP T-ALL treated with dasatinib plus 4-drug induction compared to those treated with 4-drug induction in CCCG-ALL-2020	The expected study duration is approximately 5 years.	For this objective a one-sided comparison of probabilities (proportions) will be made. Let p1 and p2 be the probability of aciieving negative EOI MRD on the CCCG-ALL-2020 (historical control) and the current study respectively, then the one-sided alternative hypothesis H0: p2=p1 vs. H1: p2\>p1 will be tested. The procedure of two-sample comparison of proportions with the Z-statistic (Normal approximation) will be applied.; The current CCCG-ALL2020 data show that among 573 evaluable patients 510 (89%) achaived negative EOI MRD. Benchmarking on these as historical data, a total sample size of n=550 and interim sample size n1=300 provides sufficient popwer for the planned analyses outlined above if the true MRD negativity probability is 0.92 or higher, as shown in the table below.; An interim analysis at n1=300 evaluable patients will be conducted for possible abstract submission or publication.
For non-ETP T-ALL patients with positive measurable residual diseases (MRD) on day 46, to compare MRD-negativity rate before consolidation between those receiving single agent homoharringtonine at dose of 1mg/m2 vs. 2mg/m2 for 7 days	The expected study duration is approximately 5 years.	The comparison will be condicted by testing the two-sided hypothesis H0: p1=p2 vs. H1: p1≠p2, using the Z test (normal approximation) at alpha=0.10 level.; The investigators anticipate approximately 40 patients available to be randomized. The participants will be randomized at 1:1 ratio into the two treatment arms, with 20 patients per arm. Stratified block-wise randomization will be applied with block size of 4. The randomization will be stratified by the EOI MRD level as \<1% and \>=1%.
End of induction (EOI) measurable residual diseases (MRD)-negativity rate with venetoclax plus 3-drug induction, compared to those treated with 4-drug induction on CCCG-ALL-2020 in treating ETP/near-ETP T-ALL.	The expected study duration is approximately 5 years.	The investigators anticipate at least 60 evaluable ETP participants. The analysis will be conducted by testing H0: p2=p1 vs. H1: p2\>p1, where p1, p2 are MRD-negative probabilities in the CCCG-ALL-2020 and the current study respectively. The Z-statistic (normal approximation) based procedure will be applied.
In interim therapies 2 and 4, venetoclax replaced daunorubicin to evaluate whether this change could improve event-free survival compared to similar patients on CCCG-ALL-2020 in treating ETP/near-ETP T-ALL.	The expected study duration is approximately 5 years.	The investigators anticipate at least 60 evaluable participants. The event-free survival function will be estimated by the Kaplan-Meier method. Comparison will be conducted using the two-sided log-rank test.

Secondary Outcome Measures

Name	Time	Method
Event-free survival (EFS) of patients treated with this therapy, in comparison to historical regimens.	Approximately 6.5 years.	The EFS functions will be estimated by the Kaplan-Meier method along with 95% confidence intervals at specified timepoints (e.g., 1, 3, 5 years since diagnosis). Standard error will be estimated using the default procedure in R. Follow up of the historical comparison cohort (CCCG-ALL-2020 and 2015) will continue during the course of the current trial. Comparisons of EFS will be performed using two-sided log-rank test. Multivariable regression modeling including trial (CCCGALL-2025 vs. 2020 or 2015) and other known prognostic factors as main effects may also be performed, using the Cox models.
Overall survival (OS) of patients treated with this therapy, in comparison to historical regimens	Approximately 6.5 years.	The OS functions will be estimated by the Kaplan-Meier method along with 95% confidence intervals at specified timepoints (e.g., 1, 3, 5 years since diagnosis). Comparison of OS functions will be conducted using the two-sided log-rank test. Standard error will be estimated using the default procedure in R. Follow up of the historical comparison cohort (CCCG-ALL-2020 and 2015) will continue during the course of the current trial. Comparisons of OS will be performed using two-sided log-rank test. Multivariable regression modeling including trial (CCCGALL-2025 vs. 2020 or 2015) and other known prognostic factors as main effects may also be performed, using the Cox models.
Cumulative incidence of relapse (CIR) of this therapy, in comparison to historical regimens.	Approximately 6.5 years.	CIR functions of relapse will be estimated by the Kalbafleisch-Prentice method. Follow up of the historical comparison cohort (CCCG-ALL-2020 and 2015) will continue during the course of the current trial. Comparisons of CIR will be performed by Gray's test. Multivariable regression modeling including trial (CCCGALL-2025 vs. 2020 or 2015) and other known prognostic factors as main effects may also be performed, using the Fine-Gray models.
Incidence of Grade 4 Treatment-Emergent Adverse Events (TEAE) associated with venetoclax and homoharringtonine	Up to 30 days after last dose of study treatment	Proportions of grade-4 TEAEs in each treatment phase will be estimated by the sample proportions along with exact 95% confidence intervals. Cumulative incidences of various grade-3 or higher AEs throughout therapy will be estimated by the Kalbafleisch-Prentice method; death, relapse and other events rendering off therapy before completion are regarded as competing risks.

Trial Locations

Locations (26)

Anhui Medical University Second Affiliated Hospital; 🇨🇳 Hefei, Anhui, China

Anhui Provincial Children's Hospital; 🇨🇳 Hefei, Anhui, China

Chongqing Medical University Affiliated Children's Hospital; 🇨🇳 Chongqing, Chongqing, China

Fujian Medical University Union Hospital; 🇨🇳 Fuzhou, Fujian, China

Guangzhou Women and Children's Medical Center; 🇨🇳 Guangzhou, Guangdong, China

Nanfang Hospital, Southern Medical University; 🇨🇳 Guangzhou, Guangdong, China

The People's Hospital of Guangxi Zhuang Autonomous Region; 🇨🇳 Nanning, Guangxi, China

The Affiliated Hospital of Guizhou Medical University; 🇨🇳 Guiyang, Guizhou, China

Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology; 🇨🇳 Wuhan, Hubei, China

Union Hospital of Tongji Medical College, Huazhong University of Science and Technology; 🇨🇳 Wuhan, Hubei, China

Wuhan Children's Hospital; 🇨🇳 Wuhan, Hubei, China

Hunan Children's Hospital; 🇨🇳 Changsha, Hunan, China

Xiangya Hospital Central South University; 🇨🇳 Changsha, Hunan, China

Nanjing Children's Hospital Affiliated to Nanjing Medical University; 🇨🇳 Nanjin, Jiangsu, China

Children's Hospital of Soochow University; 🇨🇳 Suzhou, Jiangsu, China

Jiangxi Provincial Children's Hospital; 🇨🇳 Nanchang, Jiangxi, China

Qilu Hospital of Shandong University; 🇨🇳 Jinan, Shandong, China

Affiliated Hospital of Qingdao University; 🇨🇳 Qingdao, Shandong, China

Children's Hospital of Fudan University; 🇨🇳 Shanghai, Shanghai, China

Shanghai Children's Hospital; 🇨🇳 Shanghai, Shanghai, China

Shanghai Children's Medical Cener, Shanghai Jiao Tong University School of Medicine; 🇨🇳 Shanghai, Shanghai, China

Xi'an Northwest Women and Children Hospital; 🇨🇳 Xi'an, Shanxi, China

Shenzhen Children's Hospital; 🇨🇳 Shenzhen, Shenzhen, China

West China Second University Hospital; 🇨🇳 Chengdu, Sichuan, China

Institute of Hematology and Blood Diseases Hospital, CAMS & PUMC; 🇨🇳 Tianjin, Tianjin, China

Hong Kong Children's Hospital; 🇭🇰 Hong Kong, Hong Kong