Ifosfamide
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
Ifosfamide: Female breast carcinoma
One-Sentence Summary
Ifosfamide is an alkylating chemotherapy drug that has been marketed in Canada as IFEX for cancer treatment. The TxGNN model predicts it may be effective for female breast carcinoma, with 6 registered clinical trials and 20 publications in this direction. None of the trials is a completed Phase 2/3 randomised study, so the evidence is encouraging but not conclusive.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not recorded in the local data |
| Predicted New Indication | Female breast carcinoma |
| TxGNN Prediction Score | 0.9991 |
| Evidence Level | L5. No completed Phase 2/3 RCT was found. Support comes from Phase 2 studies, cohorts and reviews. |
| Canada Market Status | Marketed (marketed DINs: 2 of 2) |
| Number of DINs | 2 (marketed: 2) |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Ifosfamide is a prodrug. Liver cytochrome P450 enzymes convert it to isophosphoramide mustard, which cross-links DNA and triggers cell death in rapidly dividing cells. Detailed mechanism-of-action data are not available in the compiled drug record, but this activation pathway is well described in the literature.
Breast cancer cells divide rapidly, so DNA-damaging agents are mechanistically applicable. Ifosfamide is an analogue of cyclophosphamide, which is already used in breast cancer regimens. Several older Phase 2 studies tested ifosfamide alone or combined with vinorelbine, mitoxantrone, etoposide or paclitaxel in metastatic breast cancer. A review reports single-agent response rates of 7–30% in pretreated patients, with higher rates in combinations.
Ifosfamide is not a standard breast cancer drug, and no Phase 3 trial supports it in this setting. The prediction is biologically plausible, but the evidence is early-phase and mostly dated.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00026078 | Phase 2 | Unknown | 42 | Docetaxel plus ifosfamide as first-line therapy in metastatic breast cancer. This is the most directly relevant trial. |
| NCT00012311 | Phase 2 | Unknown | Not reported | Randomised comparison of multi-cycle high-dose chemotherapy with stem cell support versus optimised conventional chemotherapy in metastatic breast cancer. Ifosfamide’s individual contribution cannot be isolated. |
| NCT00002854 | Phase 1 | Completed | 33 | Sequential high-dose cisplatin, cyclophosphamide, etoposide, ifosfamide, carboplatin and paclitaxel with stem cell support in advanced cancer. Tests feasibility. |
| NCT00006032 | Phase 2 | Terminated | Not reported | Intensive topotecan, ifosfamide/mesna and etoposide with autologous stem cell rescue in metastatic breast cancer. The combination confounds the signal. |
| NCT00003086 | Phase 1/2 | Terminated | 12 | Samarium-153 with double autologous transplant in stage IV breast cancer. Ifosfamide is not the focus. |
| NCT00020722 | Phase 2 | Terminated | 7 | Activated T cells after stem cell transplant in stage IV breast cancer. Ifosfamide is peripheral to the intervention. |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 8918497 | 1996 | Phase 2 trial | J Clin Oncol | Ifosfamide plus vinorelbine as first-line chemotherapy for metastatic breast cancer, evaluating efficacy and toxicity. |
| 8445421 | 1993 | Phase 2 trial | J Clin Oncol | Ifosfamide plus mitoxantrone as first-line chemotherapy for metastatic breast carcinoma. |
| 11932893 | 2002 | Phase 2 trial | Cancer | Paclitaxel (24-hour infusion) plus ifosfamide in anthracycline-resistant metastatic breast carcinoma. |
| 14586149 | 2003 | Review | Oncology | Ifosfamide in advanced breast cancer. Mesna has reduced urotoxicity, single-agent response rates are 7–30% in pretreated patients, and combinations look more promising. |
| 39306877 | 2024 | Cohort | Curr Probl Cancer | Experience with ifosfamide-based first-line chemotherapy in metaplastic breast cancer, a rare variant that responds poorly to standard anthracycline and taxane regimens. |
| 9226029 | 1997 | Clinical study | Tumori | Ifosfamide plus etoposide in previously treated advanced breast cancer, assessing response and toxicity. |
| 2347057 | 1990 | Clinical study | Cancer Chemother Pharmacol | Ifosfamide substituted for cyclophosphamide in the CMF regimen in 25 patients with CMF-refractory or relapsed breast cancer. |
| 1390313 | 1992 | Review | Ann Oncol | Use of ifosfamide in breast cancer. Early monotherapy studies reported about a 20% objective response. |
| 1720382 | 1991 | Review | Drugs | Review of ifosfamide/mesna activity, pharmacokinetics and efficacy across cancers. Mesna has almost eliminated haemorrhagic cystitis. |
| 14970873 | 2004 | Mechanism study | Br J Cancer | CYP3A4, CYP2C9 and CYP2B6 expression and ifosfamide metabolism in breast cancer tissue. Shows the tumour can activate the drug locally. |
Canada Market Information
| DIN | Product Name | Status |
|---|---|---|
| 02241356 | IFEX | Valid (single-ingredient) |
| 02241357 | IFEX | Valid (single-ingredient) |
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Conventional cytotoxic (oxazaphosphorine alkylating agent) |
| Emetogenicity Classification | Moderate to high, depending on dose |
| Monitoring Items | CBC with differential, renal function and electrolytes (including potassium), liver function and bilirubin, urinalysis for haematuria, and neurological status |
| Handling Protection | Must follow cytotoxic drug handling regulations. Mesna uroprotection is routinely co-administered. |
The emetogenicity and handling entries reflect general drug-class knowledge. Please also refer to the package insert warnings and precautions.
Safety Considerations
- Disease-related cautions (knowledge graph, not label text): The knowledge graph flags ifosfamide as contraindicated or to be used with caution in kidney disease, Fanconi renotubular syndrome, renal tubular acidosis, liver disease, hyperbilirubinaemia (including Gilbert syndrome), gallbladder disease, pyoureter, thrombocytopenia, leukopenia, anaemia (including macrocytic anaemia) and potassium deficiency. These come from knowledge-graph edges and should be verified against the official label.
- Drug interactions: 100 interactions were recorded. The 20 reviewed are mostly Moderate, with one Minor (levofloxacin). The main ones are:
- Nephrotoxic or aminoglycoside agents: amphotericin B (including the lipid complex), kanamycin, neomycin
- Sulfonylureas and glinides: chlorpropamide, glimepiride, glipizide, glyburide, tolazamide, acetohexamide, nateglinide, repaglinide
- Antiemetic and CNS-active agents: aprepitant, metoclopramide, dronabinol, nabilone, scopolamine, bupropion, morphine
Health Canada package insert warnings and contraindications were not captured in the compiled data. Please refer to the package insert for the authoritative safety information.
Conclusion and Next Steps
Decision: Hold
Rationale:
- The mechanism is plausible and there is a long history of Phase 2 activity in metastatic breast cancer. However, no completed Phase 2/3 randomised trial isolates ifosfamide’s benefit, the trials are old or have unknown or terminated status, and ifosfamide is not a standard breast cancer agent.
- The safety burden is significant: marrow suppression, nephrotoxicity, neurotoxicity and urotoxicity.
- Among the other TxGNN predictions for ifosfamide, rhabdomyosarcoma has much stronger support. It has multiple completed Phase 3 trials of ifosfamide-containing regimens in soft tissue sarcoma and a consistent literature, and was graded L1 and “Proceed with Guardrails” in the compiled data. That Phase 3 evidence is in the broader sarcoma population, not rhabdomyosarcoma alone. It may be a higher-priority repurposing direction than breast carcinoma.
To proceed, the following is needed:
- Health Canada package insert warnings and contraindications, to complete the safety screen
- Mechanism-of-action data in a structured source (DrugBank)
- A systematic review or pooled analysis of ifosfamide combinations in metastatic breast cancer, especially metaplastic and anthracycline-resistant subtypes
- Updated status of the Phase 2 trial NCT00026078 and any newer comparative trials
- A monitoring and guardrail plan covering mesna, renal, neurological and marrow monitoring, and cumulative-dose and secondary-malignancy limits
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.