Prevention of Paclitaxel-induced Neuropathic Pain in Patients With Planned Paclitaxel Chemotherapy (PrevTel)

Study Overview
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Brief Summary
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Phase IIa clinical trial will be conducted with patients requiring in-label paclitaxel-chemotherapy due to ovarian or breast cancer. The efficacy of a 12-week telmisartan treatment, starting one week before planned paclitaxel-administration to prevent PIPNP (paclitaxel-induced peripheral neuropathic pain) will be assessed by measurement of occurrence of clinical symptoms of PIPNP as well as lipid profiles

Detailed Description
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Paclitaxel is a cytostatic drug that is widely used for the first-line treatment of breast- and ovarian cancer and causes neuropathic pain in up to 87% of treated patients Treating mice with telmisartan causes a strong reduction of PIPNP, thus indicating that telmisartan may be a promising pharmacological treatment option for PIPNP in patients. It is proposed that telmisartan reduces the inflammatory component of PIPNP. Telmisartan has a good risk profile, low occurrence of side effects and is generally well tolerated in patients.These collective characteristics make it a suitable, already approved and appropriate substance for combination therapy with paclitaxel. Therefore, telmisartan is a promising candidate to potentially prevent PIPNP in patients whose safety profile is well known due to preclinical and clinical trials for the indication of hypertension and coronary heart disease. Moreover, due to its mechanisms it might as well reduce symptoms of PIPNP sufficiently without severe side effects. To validate these observations clinically, this phase IIa clinical trial will be conducted with breast and ovarian cancer patients requiring in-label paclitaxel-chemotherapy. The efficacy of a 12-week telmisartan treatment initiated before the first administration of paclitaxel to prevent PIPNP will be assessed. Moreover, beside lipid profiles, quantitative sensoric testing of pain characteristics in focus on biomarker detection and development that may be useful for a precision medicine approach will be assessed.

Official Title
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Prevention of Paclitaxel-induced Neuropathic Pain by Telmisartan in Patients With Planned Paclitaxel Chemotherapy Due to Ovarian or Breast Cancer (PrevTel)

Conditions
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Neuropathic Pain, Chemotherapy Effect

Intervention / Treatment
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* Drug: Telmisartan tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with a diagnosis of ovarian or breast cancer who are clinically eligible for paclitaxel therapy and for whom paclitaxel chemotherapy is planned (with use of standard treatment) in clinical routine care. Female patients ≥ 18 years and ≤ 80 years The patient must have completed radiotherapy or surgery for central nervous system (CNS) metastases > 2 weeks prior to screening (SCR). Patients must be neurologically stable, having no new neurological deficits on clinical examination, and no new findings on CNS imaging as documented in clinical routine care. If patients require steroids for management of CNS metastases, they must have been on a stable dose of steroids for 2 weeks preceding SCR. Written informed consent obtained prior to the initiation of any protocol-required procedures Willingness to comply to study procedures and study protocol Exclusion Criteria: Previously diagnosed or current peripheral neuropathic pain Other severe pain that might impair the assessment of neuropathic pain DN4 score ≥ 4 Previous chemotherapy (incl. paclitaxel) within the last 5 years (treatment with cyclophosphamide and an anthracycline as part of an ongoing adjuvant or neo-adjuvant regimen is allowed) Current or planned combinational chemotherapy-regimens, e.g., with platinum-based drugs (Her2 antibodies are allowed; paclitaxel combination with trastuzumab +/- pertuzumab is allowed) All primary central nervous system (CNS) tumors or symptomatic CNS metastases that are neurologically unstable (Note: Only patients with controlled CNS metastases may participate in this trial) Previously reported intolerance to Angiotensin II (AT1) -receptor-blockers Hypotension (blood pressure < 110/70 mmHg; median from 3 measurements; start of measurement after patients has been seated for at least 5 minutes) Current intake of aliskiren, digoxin or Angiotensin-converting-enzyme (ACE)-inhibitors at baseline (BL) (treatment change from ACE-inhibitors to telmisartan is allowed, with treatment start of telmisartan at BL) Current intake of antidepressants (e.g., amitriptylin), antiepileptics (e.g., gabapentin, pregabalin, lamotrigine), duloxetine, glutamin, vitamin E Current intake of telmisartan at SCR Insufficient hepatic or renal function at SCR: Serum creatinine ≥ 1.5 x upper limit of normal (ULN) Total bilirubin > 1.5 x ULN Glutamate-Oxalacetete-Transaminase/Glutamate-Pyruvate-Transaminase (GOT/GPT) ≥ 3 x ULN or >5 in case of documented liver metastasis Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection) History of or current severe psychological illness or condition Uncontrolled coronary angina or symptomatic congestive heart failure (NYHA (New York Heart Association) Class III or IV) Patients with current malignant disease, other than that being treated in this study. Exceptions to this exclusion criterion include the following: malignancies that were treated curatively and have not recurred within 2 years prior to SCR; completely resected basal cell and squamous cell skin cancers; and completely resected carcinoma in situ of any type Evidence of significant uncontrolled concomitant diseases or serious and/or uncontrolled diseases that are likely to interfere with the evaluation of the patient's safety and of the study outcome History of or evidence of current active Hepatitis B or C or Human Immunodeficiency Virus (HIV) infection with documentation not older than 8 weeks (due to blood sample processing for lipid profile analysis)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Interventional Model Description: monocentric, open label, single-arm trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention with Telmisartan<br>Telmisartan (open), 80 mg daily p.o. (after run-in phase with 40 mg for 7 days). for 12 weeks | Drug: Telmisartan tablets<br>* 12 weeks treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| efficacy of telmisartan to prevent new onset of Paclitaxel- induced peripheral neuropathic pain (PIPNP) | Proportion of patients without onset of PIPNP measured by median Quality of life questionaire (doleur neuropathic questionnaire) DN4, DN4 < 4 | week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with new onset of PIPNP | Douleur Neuropathique 4 (DN4) questionnaire (DN4 ≥ 4) higher score means more pain, minimum 0 to maximum 10 points | Day 14 | 
| Proportion of patients with new onset of PIPNP | DN4 questionnaire (DN4 ≥ 4) higher score means more pain, minimum 0 to maximum 10 points | Day 28 | 
| Proportion of patients with new onset of PIPNP | DN4 questionnaire (DN4 ≥ 4) higher score means more pain, minimum 0 to maximum 10 points | Day 49 | 
| Proportion of patients with new onset of PIPNP | DN4 questionnaire DN4 ≥ 4 | Day 70 | 
| Proportion of patients with new onset of PIPNP | DN4 questionnaire DN4 ≥ 4 higher score means more pain, minimum 0 to maximum 10 points | Day 84 | 
| Change of pain intensity to baseline - Paindetect | PainDetect questionnaire, higher score means more pain, minimum 0 to 38 maximum | Day 14 | 
| Change of pain intensity to baseline - Paindetect | PainDetect questionnaire, higher score means more pain, minimum 0 to 38 maximum | Day 28 | 
| Change of pain intensity to baseline - Paindetect | PainDetect questionnaire, higher score means more pain, minimum 0 to 38 maximum | Day 49 | 
| Change of pain intensity to baseline - Paindetect | PainDetect questionnaire, higher score means more pain, minimum 0 to 38 maximum | Day 70 | 
| Change of pain intensity to baseline - Paindetect | PainDetect questionnaire, higher score means more pain, minimum 0 to 38 maximum | Day 84 | 
| Change of pain intensity to baseline - VAS | patient global pain visual analogue scale (VAS-Pain), minimum 0 to 10, higher score means more pain | Day 14 | 
| Change of pain intensity to baseline - VAS | patient global pain visual analogue scale (VAS-Pain), minimum 0 to 10, higher score means more pain | Day 28 | 
| Change of pain intensity to baseline - VAS | patient global pain visual analogue scale (VAS-Pain), minimum 0 to 10, higher score means more pain | Day 49 | 
| Change of pain intensity to baseline - VAS | patient global pain visual analogue scale (VAS-Pain), minimum 0 to 10, higher score means more pain | Day 70 | 
| Change of pain intensity to baseline - VAS | patient global pain visual analogue scale (VAS-Pain), minimum 0 to 10, higher score means more pain | Day 84 | 
| Change in pain pattern to baseline | PainDetect questionnaire, higher score means more pain, minimum 0 to 38 maximum | Day 14 | 
| Change in pain pattern to baseline | PainDetect questionnaire, higher score means more pain, minimum 0 to 38 maximum | Day 28 | 
| Change in pain pattern to baseline | PainDetect questionnaire, higher score means more pain, minimum 0 to 38 maximum | Day 49 | 
| Change in pain pattern to baseline | PainDetect questionnaire, higher score means more pain, minimum 0 to 38 maximum | Day 70 | 
| Change in pain pattern to baseline | PainDetect questionnaire, higher score means more pain, minimum 0 to 38 maximum | Day 84 | 
| Change of pain quality to baseline | PainDetect questionnaire, higher score means more pain, minimum 0 to 38 maximum | Day 14 | 
| Change of pain quality to baseline | PainDetect questionnaire, higher score means more pain, minimum 0 to 38 maximum | Day 28 | 
| Change of pain quality to baseline | PainDetect questionnaire, higher score means more pain, minimum 0 to 38 maximum | Day 49 | 
| Change of pain quality to baseline | PainDetect questionnaire, higher score means more pain, minimum 0 to 38 maximum | Day 70 | 
| Change of pain quality to baseline | PainDetect questionnaire, higher score means more pain, minimum 0 to 38 maximum | Day 84 | 
| Change in quality of life (QoL) to baseline | Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX questionnaire) - some items are reverse scored. Subscale scores, total scores possible | Day 14 | 
| Change in quality of life (QoL) to baseline | Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX questionnaire) - some items are reverse scored. Subscale scores, total scores possible | Day 49 | 
| Change in quality of life (QoL) to baseline | Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX questionnaire) - some items are reverse scored. Subscale scores, total scores possible | Day 28 | 
| Change in quality of life (QoL) to baseline | Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX questionnaire) - some items are reverse scored. Subscale scores, total scores possible | Day 70 | 
| Change in quality of life (QoL) to baseline | Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX questionnaire) - some items are reverse scored. Subscale scores, total scores possible | Day 84 | 
| cumulative incidence of neuropathic pain | documented by physician | throughout study treatment - 12 weeks | 
| Quantification of the incidence of paclitaxel-associated acute pain syndrome (PAPS) | documented by physician | throughout study treatment - 12 weeks | 
| proportion of patients in need of PIPNP symptomatic therapy | determined by treating physician - documented in case report form | throughout study treatment - 12 weeks | 
| Assessment of frequency of adverse events | determined by using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 | throughout study treatment - 12 weeks | 
| Assessment of severity of adverse events | determined by using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 | throughout study treatment - 12 weeks | 
| Assessment relatedness of adverse events | determined by using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 | throughout study treatment - 12 weeks | 
| Assessment of type of adverse events | determined by using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 | throughout study treatment - 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chemotherapy induced peripheral neuropathic pain, breast cancer; ovarian cancer; paclitaxel