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

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

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

Study Overview

• Status: Recruiting
• Conditions: Neuropathic Pain; Chemotherapy Effect
• Intervention / Treatment: Drug: Telmisartan tablets

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 35
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Christin Jonetzko; Phone Number: 00 49 69 6301 80231; Email: christin.jonetzko@itmp.fraunhofer.de
• Study Contact Backup: Name: Tanja Rossmanith, PhD; Email: tanja.rossmanith@itmp.fraunhofer.de

Study Locations

• Germany
  • Frankfurt, Germany, 60590
    • Recruiting
    • Department of Haematology/Medical Onkology, University Hospital, Goethe-University Frankfurt
    • Contact: Martin Sebastian, MD; Email: Martin.Sebastian@kgu.de
    • Principal Investigator: Martin Sebastian, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Dr. Frank Behrens
• Collaborators: Johann Wolfgang Goethe University Hospital
• Investigators: Principal Investigator: Martin Sebastian, MD, Department of Haematology/Medical Onkology, University Hospital, Goethe-University Frankfurt

Study record dates

Study Major Dates

• Study Start (Actual): April 9, 2020
• Primary Completion (Anticipated): June 1, 2023
• Study Completion (Anticipated): June 1, 2023

Study Registration Dates

• First Submitted: April 4, 2022
• First Submitted That Met QC Criteria: April 4, 2022
• First Posted (Actual): April 12, 2022

Study Record Updates

• Last Update Posted (Actual): April 12, 2022
• Last Update Submitted That Met QC Criteria: April 4, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: chemotherapy induced peripheral neuropathic pain, breast cancer; ovarian cancer; paclitaxel
• Additional Relevant MeSH Terms: Nervous System Diseases; Pain; Neurologic Manifestations; Neuromuscular Diseases; Peripheral Nervous System Diseases; Neuralgia; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Telmisartan
• Other Study ID Numbers: TMP-0315-2018

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No