Study of repurposing an anti-parasitic drug as add-on therapy in Relapsed Acute Lymphoblastic Leukemia patients.

Phase 1/2

Not yet recruiting

Conditions: Acute lymphoblastic leukemia [ALL],

Registration Number: CTRI/2025/04/085391

Lead Sponsor: ICMR (INDIAN COUNCIL OF MEDICAL RESEARCH)

Brief Summary: Background: Acute leukemia, such as acute lymphoblastic leukemia (ALL) is a rare and complex disease characterized by clonal hematopoiesis and rapid growth of immature white blood cells in peripheral blood (PB) and/or bone marrow (BM). ALL accounts for over a quarter of all pediatric malignancies. While in Western countries, the survival is about 90%, in low-middle income countries (LMIC) like India, it is about 60-70%. Refractory and relapsed ALL, which forms the third most common group of childhood cancer, is a significant clinical problem and a leading cause of death in childhood cancer. R/R ALL is very difficult to treat, especially in LMICs. The outcomes of relapsed leukemia are dismal due to poor disease biology, sub-optimal efficacy of existing chemotherapy regimens, inadequate resources for BMT, and inaccessibility to newer therapies, thus necessitating translational research to understand the disease etiopathogenesis and develop innovative treatment approaches. One of the major challenges in managing R/R ALL is the failure to achieve Minimal Residual Disease (MRD) negativity, which is a key predictor of long-term remission and survival. Patients who fail to reach MRD-negative status often relapse, even after achieving Complete Remission (CR). In the past ten years, many novel therapeutic strategies such as Bi-specific T-cell Engager therapies, chimeric antigen receptor T-cells (CAR-Ts) and targeted agents have become available, which are improving the cure rates for R/R ALL. However, the accessibility of the same in LMIC settings is poor due to resource constraints and high production costs. Thus, managing relapsed/refractory (R/R) disease requires innovative strategies, including improving frontline therapy to overcome drug resistance.

In the fight against relapsed and refractory ALL, niclosamide, a drug that was once used to treat tapeworm infections, has shown promise. According to a number of studies that have extensively documented the pleiotropic effects of this drug, it may be able to target particular weaknesses in leukemia cells. Niclosamide has been reported to alter many oncogenic signaling pathways and modulate key phenomena pertinent to cancer progression such as apoptosis, autophagy and even modulation of the tumor immune microenvironment. Despite its potential, the use of niclosamide still faces a number of challenges. These include addressing possible adverse effects, better understanding its methods of action, and maximizing its delivery to cancer cells. The best niclosamide dosage, timing, and combination therapies for the treatment of ALL require more investigation. Rationale: In acute leukemia, evasion of apoptosis leads to chemotherapy resistance and treatment failure. Research on the in vivo function of apoptosis in leukemia cells and the application of anti-apoptotic medications in the management of ALL is, however, scarce. According to the initial findings of our ongoing research (ICMR Adhoc grant) on the role of the apoptosis pathway in ALL, patients with a low baseline apoptosis index have a poor post-induction remission rate. In order to treat R/R ALL, we intend to alter the apoptosis pathway using Niclosamide, a repurposed anthelminthic medication with immunomodulatory and broad anti-cancer properties. Niclosamide, a well-known anthelminthic drug with a unique mechanism of action, offers a promising therapy due to its ability to affect multiple cellular processes. By reprogramming cellular metabolism and acting as a mitochondrial uncoupler, niclosamide modulates the global epigenetic landscape, allowing it to suppress oncogenic pathways while enhancing tumor suppressor pathways. Given its capacity to target several pathways simultaneously, it may bypass the usual resistance mechanisms seen with conventional therapies, providing a novel therapeutic approach for R/R ALL. Novelty: The innovative aspect of this study lies in repurposing niclosamide, an anti-parasitic drug, as a potential therapy for R/R ALL. Unlike traditional chemotherapy, which targets rapidly dividing cells and often leads to resistance, niclosamide uniquely reprograms cellular metabolism and modulates epigenetic landscapes, offering a dual effect of inhibiting cancer-promoting pathways and activating cancer-suppressing pathways. Preclinical evidence in T-ALL xenograft models, showing activation of apoptotic markers such as cleaved caspase-3 and autophagy markers like LC3B, further highlights its novel mechanism of action. This approach could open pathways to a new class of treatments for R/R ALL, particularly in resource-limited settings where access to newly developed, expensive oncology drugs is restricted.

Expected Outcome:

It is anticipated that niclosamide will demonstrate a significant anti-leukemic effect in R/R ALL by activating both apoptotic and autophagy pathways, leading to reduced leukemic cell proliferation and improved survival outcomes in patients. Additionally, it is expected that it’s immune-modulation effect will lead to better clinical outcomes. Potentially establish niclosamide as an accessible and cost-effective therapeutic alternative for R/R ALL, especially valuable in resource-constrained environments. Biomarkers of drug response identified through the study will help in better patient selection for future studies and clinical use. Additionally, the findings may encourage further research into the metabolic reprogramming and epigenetic effects of niclosamide, expanding its applicability beyond ALL to other resistant cancer types.

Detailed Description: Not available

Recruitment & Eligibility

Status: Not Yet Recruiting

Sex: All

Target Recruitment: 61

Inclusion Criteria

Inclusion criteria for Phase I.
1. Patients with relapsed ALL to be started on salvage treatment 2. Patients planned for intensive salvage induction chemotherapy: a. Group 1: UKALL R3 or UKALL R3-like protocol b. Group 2: UKALL R3 or UKALL R3-like protocol 3. Age: Patients will be grouped according to age into: a. Group 1: 2-18 years b. Group 2: 19.
40 years 4. Both genders 5. ECOG Performance Status – 0 to 2, determined by the treating physician 6. Both with B-ALL and T-ALL patients 7. All timelines of relapse – very early, early or late relapse 8. All types of relapse.
medullary, extramedullary and combined relapse 9. Normal cardiac, renal, and liver function 10. All patients meeting the aforementioned criteria irrespective of duration of remission Inclusion criteria for Phase II.
1. Patients with relapsed ALL to be started on salvage treatment 2. Patients planned for intensive salvage induction chemotherapy: UKALL R3 or UKALL R3-Like protocol 3. Age: 2 to 40 years 4. Both genders 5. ECOG Performance Status – 0 to 2, determined by the treating physician 6. Both with B-ALL and T-ALL patients 7. All timelines of relapse – very early, early or late relapse 8. All types of relapse.
medullary, extramedullary and combined relapse 9. Normal cardiac, renal, and liver function 10. All patients meeting the aforementioned criteria irrespective of duration of remission.

Exclusion Criteria

Exclusion criteria for both Phase I and Phase II.
1. Ph-positive ALL 2. Active complicated infections, as per the discretion of the treating physician 3. HIV or Hepatitis B or C positive patients 4. Pregnant and lactating women 5. Patients on certain medications that have the potential to exhibit significant drug interactions with Niclosamide.

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
In the Phase I study, the following outcomes will be measured from assessment of Toxicities throughout 28-day study period:	PHASE I: 28 Days (daily) \| PHASE II: \| Baseline, 28 Days and 12 weeks
In the Phase II study the following will be assessed:	PHASE I: 28 Days (daily) \| PHASE II: \| Baseline, 28 Days and 12 weeks
1. Maximum tolerated dose (MTD)	PHASE I: 28 Days (daily) \| PHASE II: \| Baseline, 28 Days and 12 weeks
2. Optimal Phase 2 recommended dose (P2RD) of Niclosamide	PHASE I: 28 Days (daily) \| PHASE II: \| Baseline, 28 Days and 12 weeks
1. Response rates through assessment of Complete Remission and Minimal Residual Disease status	PHASE I: 28 Days (daily) \| PHASE II: \| Baseline, 28 Days and 12 weeks

Secondary Outcome Measures

Name	Time	Method
PHASE I:	1. Pharmacokinetic Parameters (Cmax, Tmax etc.)

Trial Locations

Locations (1): JIPMER HOSPITAL
🇮🇳
Pondicherry, PONDICHERRY, India
JIPMER HOSPITAL
🇮🇳Pondicherry, PONDICHERRY, India
Dr Smita Kayal
Principal investigator
07598118439
kayalsmita@gmail.com