Ifosfamide
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
- Ifosfamide
- Pharmacist Assessment Report
- Ifosfamide: From Unspecified Original Indication to Female Breast Carcinoma
- One-Sentence Summary
- Quick Overview
- Why is This Prediction Reasonable?
- Clinical Trial Evidence
- Literature Evidence
- Australia Market Information
- Cytotoxicity
- Safety Considerations
- Conclusion and Next Steps
- Disclaimer
Ifosfamide: From Unspecified Original Indication to Female Breast Carcinoma
One-Sentence Summary
Ifosfamide is an alkylating chemotherapy drug (an analogue of cyclophosphamide) that is registered in Australia as Holoxan, although the data compiled for this report do not include the approved indication text. The TxGNN model predicts it may be effective for female breast carcinoma, supported by 6 registered clinical trials (all Phase 1 or 2, mostly early-phase or terminated) and 20 publications. Of the 10 predicted indications, rhabdomyosarcoma has the strongest evidence base (several Phase 3 sarcoma trials), and it is discussed in the conclusion.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not available in the data compiled for this report (the ARTG entry has no indication text) |
| Predicted New Indication | Female breast carcinoma |
| TxGNN Prediction Score | 0.9991 |
| Evidence Level | L5 (as assigned in the data compiled for this report; strictly, only Phase 1/2 trials, none randomised and completed with efficacy results) |
| Australia Market Status | Listed on the PBS Schedule (1 of 1 items) – TGA (ARTG) registration status is not included in this data |
| Number of PBS Items | 1 (valid: 1) |
| Recommended Decision | Hold (research question) |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not recorded in the compiled data. From the literature, ifosfamide is a prodrug activated by hepatic cytochrome P450 enzymes to isophosphoramide mustard, which cross-links DNA and induces apoptosis in proliferating tumour cells. It is given with mesna to reduce urotoxicity.
Ifosfamide has long been known to have activity in breast cancer. Single-agent response rates of about 7 to 30% have been reported in pretreated patients, and combinations with docetaxel, vinorelbine, mitoxantrone, etoposide and paclitaxel have been tested in Phase 2 studies. It is not a standard-of-care agent for breast cancer. Activity appears most relevant in specific subsets, such as metaplastic breast cancer and malignant phyllodes tumours, where anthracycline and taxane responses are poor.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrolment | Key Findings |
|---|---|---|---|---|
| NCT00026078 | Phase 2 | Unknown | 42 | Docetaxel plus ifosfamide as first-line therapy in metastatic breast cancer; single-arm, directly tests ifosfamide |
| 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 may be part of the regimen |
| NCT00002854 | Phase 1 | Completed | 33 | Sequential high-dose cisplatin, cyclophosphamide, etoposide, ifosfamide, carboplatin and paclitaxel with stem cell support in advanced cancer; feasibility and safety only |
| NCT00006032 | Phase 2 | Terminated | Not reported | Intensive-dose topotecan, ifosfamide/mesna and etoposide with stem cell rescue in metastatic breast cancer; terminated early |
| NCT00003086 | Phase 1/2 | Terminated | 12 | Samarium-153 within a double autologous transplant in stage IV breast cancer; ifosfamide is a background component |
| NCT00020722 | Phase 2 | Terminated | 7 | Activated T cells after stem cell transplant in stage IV breast cancer; ifosfamide is not the focus |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 14586149 | 2003 | Review | Oncology | Ifosfamide in advanced breast cancer: single-agent response rates 7 to 30% in pretreated patients, with more encouraging results in combinations; mesna reduces urotoxicity |
| 1390313 | 1992 | Narrative review | Ann Oncol | History of ifosfamide in breast cancer; about 20% objective response as monotherapy |
| 39306877 | 2024 | Cohort | Curr Probl Cancer | Experience with ifosfamide-based first-line chemotherapy in metaplastic breast cancer |
| 39074497 | 2024 | Cohort | J Natl Compr Canc Netw | Adjuvant chemotherapy and long-term prognosis in malignant phyllodes tumours of the breast (propensity-matched) |
| 8918497 | 1996 | Phase 2 | J Clin Oncol | Ifosfamide plus vinorelbine as first-line therapy in metastatic breast cancer |
| 8445421 | 1993 | Phase 2 | J Clin Oncol | Ifosfamide plus mitoxantrone as first-line therapy in metastatic breast cancer |
| 17370037 | 2007 | Phase 2 | Invest New Drugs | Docetaxel-ifosfamide in HER2-non-overexpressing advanced breast cancer after prior anthracyclines |
| 11932893 | 2002 | Phase 2 | Cancer | Paclitaxel (24-hour infusion) plus ifosfamide in anthracycline-resistant metastatic breast cancer |
| 9226029 | 1997 | Clinical study | Tumori | Ifosfamide plus etoposide in previously treated advanced breast cancer |
| 1720382 | 1991 | Review | Drugs | Ifosfamide/mesna: antineoplastic activity, pharmacokinetics and efficacy across cancers |
Australia Market Information
| ARTG Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| ARTG 4448D | Holoxan | Powder for I.V. injection 1 g | Not available |
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Conventional cytotoxic (oxazaphosphorine alkylating agent) |
| Myelosuppression Risk | Please refer to the Product Information (PI); myelosuppression is a recognised effect |
| Emetogenicity Classification | Please refer to the Product Information (PI) |
| Monitoring Items | Full blood count, renal and liver function, electrolytes (including potassium), urinalysis |
| Handling Protection | Must follow cytotoxic drug handling requirements |
Safety Considerations
- Contraindication-related conditions (knowledge graph, not label text): the TxGNN knowledge graph links ifosfamide to kidney disease, liver disease, gallbladder disease, thrombocytopenia, leukopenia, anaemia, hyperbilirubinaemia (including Gilbert syndrome), potassium deficiency, renal tubular acidosis and Fanconi renotubular syndrome. These need verification against the TGA-approved PI.
- Drug interactions: 100 interactions were identified. Those listed are mostly Moderate, and Levofloxacin is listed as Minor. Examples include amphotericin B (including the lipid complex), aprepitant, bupropion, morphine, metoclopramide, scopolamine, dronabinol, nabilone, aminoglycosides (kanamycin, neomycin), and sulfonylureas and glinides (chlorpropamide, glimepiride, glipizide, glyburide, tolazamide, acetohexamide, nateglinide, repaglinide).
- Class risks noted in the literature: haemorrhagic cystitis (mesna uroprotection), nephrotoxicity, neurotoxicity, myelosuppression and secondary malignancy (including therapy-related MDS and leukaemia).
Please refer to the TGA-approved Product Information (PI) for official warnings and contraindications.
Conclusion and Next Steps
Decision: Hold (research question)
Rationale: For breast cancer, the evidence consists of small, early-phase or terminated trials and older Phase 2 studies, with no completed Phase 3 trial. Ifosfamide is not a standard-of-care agent in this setting. The high TxGNN score is supportive but not sufficient on its own.
Other predicted indications:
- Rhabdomyosarcoma (score 0.9967) has much stronger support, with Phase 3 trials of ifosfamide in soft tissue sarcoma (for example NCT00003212, n=780, and NCT00061984, n=455) and ifosfamide-based regimens in paediatric and adult rhabdomyosarcoma. The Phase 3 evidence is largely in broader soft tissue sarcoma. It is rated Proceed with Guardrails, and may be the better lead candidate for further evaluation.
- Botryoid-type embryonal rhabdomyosarcoma of the vagina is a plausible extrapolation from rhabdomyosarcoma but has only case-level evidence.
- The haematological predictions (myelodysplastic syndromes, cytopenias, anaemias, monocytic leukaemia and 5q deletion) have no supportive evidence. Ifosfamide is associated with causing myelosuppression and therapy-related MDS and leukaemia, so these are not credible therapeutic targets and should be held.
To proceed, the following is needed:
- The approved indication text from the TGA Product Information for Holoxan (ARTG 4448D), plus PI warnings and contraindications, which were not available in the compiled data (a blocking gap for safety screening)
- Mechanism of action data from DrugBank
- For breast cancer: randomised data in defined subsets (for example metaplastic breast cancer or malignant phyllodes tumours) before any further consideration
- For rhabdomyosarcoma: a review of Australian clinical guidelines and a safety monitoring plan covering nephrotoxicity, neurotoxicity, haemorrhagic cystitis, myelosuppression and secondary malignancy risk
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.