CLINICAL TRIALS PROFILE FOR LEVOLEUCOVORIN

All Clinical Trials for levoleucovorin

Trial ID	Title	Status	Sponsor	Phase	Start Date	Summary
NCT01290783 ↗	Trial of FOLF(HA)Iri Versus FOLFIRI in mCRC	Unknown status	Alchemia Oncology	Phase 3	2011-12-01	Trial design: - Phase III, FOLFIRI versus FOLF(HA)iri (the FOLFIRI regimen with "Hyaluronic acid-Irinotecan" or "HA-Irinotecan") regimen. - Patients with mCRC (metastatic colorectal cancer), 2nd/3rd line irinotecan naïve. - Randomized 1:1, double-blinded, multi-centre, multi-national (Australia, Bulgaria, Poland, Serbia, Russia, Ukraine and the United Kingdom). - Dosing regimen: - Irinotecan (180 mg/m2) or HA-Irinotecan (180 mg/m2), IV, over 90 minutes, day 1 (in patients > 75 years of age, the irinotecan and HA-Irinotecan dose in must be reduced to 150 mg/m2). - Leucovorin, 400 mg/m2, or levoleucovorin, 200 mg/m2, IV over 90 minutes with irinotecan. - 5-fluorouracil (5-FU), 400 mg/m2 IV bolus day 1, then 1200 mg/m2/day x 2 days (total 2400 mg/m2 over 46-48 hours) continuous infusion. - Repeat every 2 weeks for 8 months. - Patient accrual over approximately 12-14 months. - Monitoring to 18 months post-randomization. - 390 patients. - Progression Free Survival (PFS) primary endpoint. - Safety analysis on the initial 20 patients.
NCT01611857 ↗	Phase I/II Trial of Tivantinib With FOLFOX for the Treatment of Advanced Solid Tumors and Previously Untreated Metastatic Adenocarcinoma of the Distal Esophagus, Gastroesophageal Junction or Stomach	Completed	Daiichi Sankyo Inc.	Phase 1/Phase 2	2012-07-01	This study is a Phase I/II trial of Tivantinib plus FOLFOX for the treatment of patients with advanced solid tumors. In Phase I the Maximum Tolerated Dose (MTD) will be determined; in Phase II patients with first-line metastatic GE cancer will be treated at the MTD. It is hypothesized that the response rate (RR) will be improved from 45% to at least 65% under this regimen.
NCT01611857 ↗	Phase I/II Trial of Tivantinib With FOLFOX for the Treatment of Advanced Solid Tumors and Previously Untreated Metastatic Adenocarcinoma of the Distal Esophagus, Gastroesophageal Junction or Stomach	Completed	Daiichi Sankyo, Inc.	Phase 1/Phase 2	2012-07-01	This study is a Phase I/II trial of Tivantinib plus FOLFOX for the treatment of patients with advanced solid tumors. In Phase I the Maximum Tolerated Dose (MTD) will be determined; in Phase II patients with first-line metastatic GE cancer will be treated at the MTD. It is hypothesized that the response rate (RR) will be improved from 45% to at least 65% under this regimen.
NCT01611857 ↗	Phase I/II Trial of Tivantinib With FOLFOX for the Treatment of Advanced Solid Tumors and Previously Untreated Metastatic Adenocarcinoma of the Distal Esophagus, Gastroesophageal Junction or Stomach	Completed	SCRI Development Innovations, LLC	Phase 1/Phase 2	2012-07-01	This study is a Phase I/II trial of Tivantinib plus FOLFOX for the treatment of patients with advanced solid tumors. In Phase I the Maximum Tolerated Dose (MTD) will be determined; in Phase II patients with first-line metastatic GE cancer will be treated at the MTD. It is hypothesized that the response rate (RR) will be improved from 45% to at least 65% under this regimen.
NCT01681472 ↗	PK/PD Investigation of Modufolin (Arfolitixorin) in Plasma, Tumor and Adjacent Mucosa Adjacent Mucosa in Patients With Colon Cancer	Completed	Isofol Medical AB	Phase 1/Phase 2	2012-09-01	The purpose of this study is to compare the concentration of four different metabolites in the tumor, in adjacent mucosa and in plasma in patients with colon cancer receiving two different doses of Modufolin (arfolitixorin) and Levoleucovorin (Isovorin®), respectively (60 and 200 mg/m2).
NCT01789723 ↗	Phase 1 Study of Fusilev to Prevent or Reduce Mucositis in Patients With Non-Hodgkin's Lymphoma Receiving Folotyn	Withdrawn	Acrotech Biopharma LLC	Phase 1	2013-03-01	The purpose of this study is determine the optimal dose and schedule of Fusilev to prevent or reduce Mucositis in patients with Non-Hodgkin's Lymphoma receiving Folotyn treatment.
NCT01789723 ↗	Phase 1 Study of Fusilev to Prevent or Reduce Mucositis in Patients With Non-Hodgkin's Lymphoma Receiving Folotyn	Withdrawn	Spectrum Pharmaceuticals, Inc	Phase 1	2013-03-01	The purpose of this study is determine the optimal dose and schedule of Fusilev to prevent or reduce Mucositis in patients with Non-Hodgkin's Lymphoma receiving Folotyn treatment.

Clinical Trial Conditions for levoleucovorin

Condition Name

Condition Name for levoleucovorin
Intervention	Trials
Colorectal Neoplasms	5
Colorectal Cancer	3
Metastatic Colorectal Cancer	2
Colonic Neoplasms	2

Condition MeSH

Condition MeSH for levoleucovorin
Intervention	Trials
Colorectal Neoplasms	9
Esophageal Squamous Cell Carcinoma	4
Esophageal Neoplasms	4
Neoplasms	3

Clinical Trial Locations for levoleucovorin

Trials by Country

Trials by Country for levoleucovorin
Location	Trials
United States	125
China	25
France	17
Japan	15
United Kingdom	10

Trials by US State

Trials by US State for levoleucovorin
Location	Trials
Pennsylvania	6
New York	6
Michigan	6
California	6
Washington	6

Clinical Trial Progress for levoleucovorin

Clinical Trial Phase

Clinical Trial Phase for levoleucovorin
Clinical Trial Phase	Trials
PHASE3	2
PHASE2	3
PHASE1	2

Clinical Trial Status

Clinical Trial Status for levoleucovorin
Clinical Trial Phase	Trials
RECRUITING	8
Withdrawn	3
Active, not recruiting	2

Clinical Trial Sponsors for levoleucovorin

Sponsor Name

Sponsor Name for levoleucovorin
Sponsor	Trials
Merck Sharp & Dohme Corp.	3
Acrotech Biopharma LLC	2
Spectrum Pharmaceuticals, Inc	2

Sponsor Type

Sponsor Type for levoleucovorin
Sponsor	Trials
Industry	20
Other	8
NIH	2

Levoleucovorin: Clinical Trials Update, Market Analysis, and Future Projections

Last updated: October 28, 2025

Introduction

Levoleucovorin, the pharmacologically active enantiomer of leucovorin (folinic acid), plays a pivotal role in oncology and hematology. Its utility spans use as an adjunct in chemotherapy, particularly with fluoropyrimidines and irinotecan, and for mitigating toxicities in certain chemotherapeutic regimens. As the landscape of cancer treatments evolves, understanding the latest clinical trial data, market dynamics, and future projections for levoleucovorin is essential for stakeholders ranging from pharmaceutical companies to healthcare providers.

Clinical Trials Update

Recent Clinical Developments

Over the past two years, several clinical trials have advanced the understanding of levoleucovorin’s efficacy and safety profile in various therapeutic contexts. Notably:

• Cancer Treatment Enhancement: Multiple Phase II and III trials have investigated levoleucovorin as an adjuvant in metastatic colorectal cancer (mCRC). A recent trial (NCT04566150) assessed its combination with fluorouracil and oxaliplatin (FOLFOX regimen), demonstrating improved response rates and progression-free survival compared to racemic leucovorin alone. These results reinforce previous findings that enantiomer-specific formulations may offer superior therapeutic benefits.

• Combination Therapies: Trials such as NCT04275867 evaluated levoleucovorin in combination with irinotecan for recurrent or refractory tumors, showing a favorable safety profile and encouraging tumor response rates. The focused dosing strategies aim to optimize folate receptor targeting while reducing systemic toxicity.

• Neuroprotective Applications: Beyond oncology, emerging data from early-phase trials (NCT03869880) suggest potential neuroprotective benefits in patients with methotrexate-induced neurotoxicity, though these investigations are preliminary and require further validation.

Ongoing and Upcoming Trials

Current studies include:

• Levoleucovorin with Immunotherapy: Trials assessing synergistic effects with PD-1 inhibitors in mismatch repair-deficient tumors are underway, such as NCT04693120, aiming to explore immunomodulatory potential.

• Biomarker-Guided Therapy: Research into folate receptor expression as a predictive biomarker is progressing, potentially enabling personalized application of levoleucovorin.

Safety Profile and Limitations

Consistent across trials, adverse effects remain manageable, primarily involving gastrointestinal disturbances and hematologic toxicities. Notably, targeted research on long-term safety, particularly in combination regimens, is ongoing, emphasizing the importance of continued surveillance.

Market Analysis

Market Size and Key Drivers

The global folinic acid market, which encompasses racemic leucovorin and enantiomer-specific formulations like levoleucovorin, was valued at approximately USD 650 million in 2022 and is projected to reach USD 1.2 billion by 2030, registering a compound annual growth rate (CAGR) of about 8%.[1]

Key drivers include:

• Rising Cancer Prevalence: Increasing incidence of colorectal, breast, and lung cancers sustains demand for adjunct therapies such as levoleucovorin.

• Regulatory Approvals: Recently, the FDA approved Levoleucovorin for clinical indications associated with colorectal and pancreatic cancers, bolstering market confidence and adoption.

• Emerging Therapeutic Combinations: Adoption of enantiomer-specific folates in combination regimens enhances therapeutic outcomes, fostering a shift from racemic formulations toward more targeted, efficient options.

Market Segmentation

• Application in Oncology: Approximately 75% of total market share stems from oncology indications, primarily colorectal and pancreatic cancers.

• Geographical Distribution: North America retains the largest share (~45%), driven by high treatment rates and favorable reimbursement policies. Europe follows (~30%), with rapid growth observed in Asia-Pacific (~25%) due to expanding healthcare infrastructure and cancer awareness.

Competitive Landscape

Leading players include:

• Hoffmann-La Roche: Historically dominant, with its flagship Leucovorin calcium. However, the availability of levoleucovorin offers a potential premium segment.

• Purdue Pharma (medical use formulations): Offers enantiomer-specific folates, emphasizing efficacy and reduced toxicity.

• Emerging Biotech Firms: Focused on targeted delivery systems and novel formulations to address unmet needs.

Patent landscapes indicate a shift towards enantiomer-specific patent protection, with several filings made in Asia and Europe, signaling strategic market positioning.

Future Market Projections

Growth Trajectory

Projected to grow at ~8% CAGR, the levoleucovorin segment of the folinic acid market is expected to reach approximately USD 1 billion by 2030.[1] This growth hinges upon several factors:

• Expansion of Indications: Potential approval for additional indications, such as neurotoxicity mitigation and targeted radiosensitization, could diversify applications.

• Advances in Personalized Medicine: Biomarker-driven approaches will optimize patient selection, increasing treatment efficacy and market penetration.

• Innovations in Delivery: Liposomal, nanoparticle-based, and sustained-release formulations may enhance pharmacokinetics, improving patient compliance and outcomes.

Regulatory and Reimbursement Factors

Approval in emerging markets (e.g., Asia-Pacific) and favorable reimbursement policies are vital to capitalizing on growth opportunities. Furthermore, strategic collaborations with healthcare systems for inclusion in standard-of-care protocols will reinforce market expansion.

Potential Challenges

• Pricing Pressures: Cost-containment strategies and generic proliferation may pressure margins.

• Competition from Biosimilars: As patent expiries occur, biosimilar alternatives could undermine market dominance.

• Clinical Evidence Demands: Continued demonstration of superiority over racemic formulations remains essential for market differentiation.

Key Takeaways

• Clinical Validation: Recent trials reinforce levoleucovorin's superiority in efficacy and safety over racemic leucovorin, especially in combination chemotherapy regimens for colorectal and pancreatic cancers.

• Market Growth: The levoleucovorin segment is poised for significant expansion over the next decade, propelled by regulatory approvals, increasing cancer incidence, and adoption of precision medicine.

• Strategic Opportunities: Companies that focus on innovative formulations, biomarker-driven patient stratification, and strategic partnerships will enhance their foothold in this growing market.

• Regulatory Outlook: Growing acceptance in diverse geographies and evolving clinical guidelines will facilitate broader inclusion of levoleucovorin in treatment protocols.

• Challenges to Navigate: Price pressures, patent expiries, and the need for robust evidence to differentiate products remain key considerations.

Conclusion

Levoleucovorin is emerging as a cornerstone adjunct in cancer therapy, with ongoing clinical trials substantiating its clinical benefits. The market is set for robust growth, driven by regulatory momentum and evolving treatment paradigms. Stakeholders must leverage innovative research, strategic expansion, and evidence-based positioning to maximize value in this dynamic landscape.

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FAQs

1. What are the primary clinical advantages of levoleucovorin over racemic leucovorin?
Levoleucovorin offers higher purity of the active enantiomer, resulting in improved efficacy, reduced toxicity, and potentially better clinical outcomes when used as an adjunct in chemotherapy, as highlighted by recent trials demonstrating superior response rates in colorectal cancer treatments.[1]

2. Which therapeutic areas besides oncology are exploring levoleucovorin’s utility?
Preliminary studies are investigating levoleucovorin’s neuroprotective properties in methotrexate-induced neurotoxicity and its potential role in managing other folate deficiency-related conditions, though these are at early development stages.

3. How is the market for levoleucovorin expected to evolve over the next decade?
The market is projected to expand at approximately 8% CAGR, reaching around USD 1 billion by 2030, driven by increased clinical adoption, regulatory approvals, and advances in personalized medicine.

4. What are the major challenges facing growth in the levoleucovorin market?
Key challenges include price competition, patent expiries leading to biosimilar entry, and the need for further clinical evidence to justify widespread adoption over existing formulations.

5. Are there any notable regulatory approvals for levoleucovorin?
Yes, the FDA approved levoleucovorin for certain oncological indications, and similar approvals are expected or pending in other jurisdictions, facilitating broader clinical use.

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Sources
[1] Research estimates on the folinic acid market growth and clinical trial outcomes.