A Study of Topical Pirenzepine or Placebo in Oncology Patients With Chemotherapy Induced Peripheral Neuropathy

This is a randomized, double-blind, placebo-controlled adaptive study of the safety, tolerability, and exploratory efficacy of once-daily topical WST-057 administered for up to 19 weeks (or up to 24 weeks for subjects who experience a chemotherapy dose delay) to subjects who are also receiving 6 cycles (3 weeks apart) of Carboplatin AUC 5-6 and Paclitaxel 175 mg/m2 (with dose adjustment per institutional guidelines permitted).

This is a randomized, double-blind, placebo-controlled adaptive study of the safety, tolerability, and exploratory efficacy of once-daily topical WST-057 administered for up to 19 weeks (or up to 24 weeks for subjects who experience a chemotherapy dose delay) to subjects who are also receiving 6 cycles (3 weeks apart) of Carboplatin AUC 5-6 and Paclitaxel 175 mg/m2 (with dose adjustment per institutional guidelines permitted). A Data Safety Monitoring Committee will review the safety data for all patients upon the completion of the first 10 patients. An interim analysis for safety and futility (primary and secondary endpoints) will be conducted after the first 20 subjects complete the trial. Based on this analysis an additional 20 subjects will be randomized and the power assessed. Depending on the statistical power after 40 subjects complete, a determination will be made as to whether or not to continue the recruitment up to a maximum of 60 subjects' completing the study.

Eligibility Criteria:
Inclusion Criteria:

1. Males and females, ages \> 18 years and older.
2. Scheduled to undergo chemotherapy for an advanced or metastatic (stage 3 or 4) solid tumor with carboplatin and paclitaxel for 6 cycles of treatment. Treatment with immunotherapy agents Avastin (bevacizumab) and/or Keytruda (pembrolizumab) is permitted.
3. Ability to sign informed consent and understand the nature of a placebo-controlled trial.
4. ECOG Performance Status (PS) of 0, 1, or 2.
5. Ability to complete patient reported outcome questionnaires by themselves.
6. Life expectancy ≥ 6 months
7. Females should be either not of childbearing potential as a result of surgery or menopause (1 year after onset), or of childbearing potential and must be practicing a highly effective medically acceptable method of contraception (as defined in section 8.4.4.1), including abstinence; hormonal contraceptives (e.g., combined oral contraceptives, patch, vaginal ring, injectables, and implants); intrauterine device or intrauterine system; or vasectomy (partner), for at least 1 month before the screening visit and for 1 month after the last dose of study medication. If access or use of a highly effective medically acceptable method of contraception is not achievable, then a combination of barrier methods (e.g., male condom, female condom, cervical cap, diaphragm, contraceptive sponge) is acceptable. Eligible female subjects must also have a negative pregnancy test at the screening and baseline visit.
8. Males must agree to the use an acceptable form of contraception (as defined in section 8.4.4.1) during sexual contact with a pregnant female or a female of childbearing potential while participating in the study (e.g., male condom with diaphragm, male condom with cervical cap, or male condom in association with spermicide).
9. If diabetic, be on stable antidiabetic treatment (\> 2 months prior to screening) (oral or injectable antidiabetic therapy and/or lifestyle) that is not anticipated to change during the course of the study, except if medically required.
10. Fluency (oral and written) in the language in which the standardized tests will be administered

Exclusion Criteria:

1. Pre-existing history (with or without current symptoms) in medical history of any type of peripheral neuropathy due to any cause other than prior chemotherapy (diabetes, alcohol, toxins, neurotoxic treatments, hereditary, autoimmune, etc.).
2. Anyone with prior history of severe paclitaxel hypersensitivity (including anaphylaxis) should be excluded from study enrollment. Pre-treatment is per local standard of care guidelines to prevent a paclitaxel hypersensitivity reaction. Absolute Neutrophil Count (ANC) must be at least 1500 cells/mm3 prior to paclitaxel treatment.
3. Currently taking regular pain medications i.e., gabapentin, pregabalin, amitriptyline or duloxetine. (Exception: opioids, given for the short-term treatment i.e., malignant pain is acceptable. Opioids prescribed for neuropathic pain is excluded).
4. Clinically significant active macrovascular disease, including a) myocardial infarction or cerebrovascular event in the prior 6 months, b) angioplasty or stenting of coronary arteries or coronary artery bypass surgery within the past \< 12 months (valve replacements are permitted as long as patient has fully recovered from the surgery), c) diagnosis of congestive heart failure of any NY heart class I-IV, d) stable or progressive angina pectoris.
5. Other medical conditions, which in the opinion of the treating physician/allied health professional would make this protocol unreasonably hazardous for the patient.
6. Vitamin E supplementation (2R-α-tocopherol or equivalent) for any reason \> 225 IU (approximately 150mg)/day ≤ 30 days prior to randomization.
7. Any of the following: pregnant women, nursing women and men or women of childbearing potential who are unwilling to employ adequate contraception (as defined in section 8.4.4.1).
8. Head or neck cancers.
9. Scheduled to undergo radiation therapy while on study.
10. History of hemorrhagic stroke.
11. Proliferative retinopathy or maculopathy requiring acute treatment.
12. Patients requiring dialysis.
13. Presence of clinically significant peripheral or autonomic neuropathy.
14. Current use local (topical) anesthetics or analgesics including lidocaine, capsaicin, cannabinoid (CBD) oil/products, or compounded topical pharmaceutical agents.
15. Uncontrolled treated/untreated hypertension (systolic blood pressure \[BP\] ≥ 180 or diastolic BP ≥ 100 at screening).
16. Amputations of lower extremities or presence of foot ulcers.
17. Uncontrolled or untreated hypothyroidism.
18. Active and/or systemic infections (e.g., HIV, hepatitis C, tuberculosis, syphilis), or a history of severe infection during the 30 days prior to screening.
19. Clinically significant gastric emptying abnormality (e.g., severe gastroparesis).
20. Clinically significant urinary retention or an enlarged prostate.
21. Uncontrolled glaucoma.
22. Other clinically significant, active or progressive (over the past 12 months) disease of the cardiovascular, gastrointestinal, pulmonary, renal, dermatologic, neurologic, genitourinary, endocrine, rheumatologic or hematologic systems that, in the opinion of the Investigator, would compromise the subject's participation in the study, might confound the results of the study, or pose additional risk in administering the study drug.
23. New treatment with (\< 3 months) vitamins and supplements at the discretion of the PI.
24. Known or suspected history of alcohol or substance abuse (a stable and regular use of medical marijuana for non-neuropathic indications is acceptable).
25. Mental incapacity, unwillingness, or language barrier precluding adequate understanding of or cooperation with the study.
26. Women of childbearing potential must have a negative pregnancy test at screening and baseline and must agree to use adequate contraceptive methods (as defined in section 8.4.4.1) during the study and for 1 month after the last dose of study drug (see inclusion criterion 7).
27. History of allergy or hypersensitivity to anticholinergics or any of the components of the investigational product formulations (pirenzepine, coconut oil, ethanol, dimethyl sulfoxide (DMSO), surfactants, propylene glycol, etc.).
28. History of sensitive skin, as defined by a requirement to use soap and skin products formulated for "sensitive skin," as determined by the Investigator.
29. Currently taking any medicines to treat overactive bladder (anticholinergic agents, such as Gelnique), or antispasmodics.
30. Inability to perform screening or baseline assessments.

    Patients with any condition that could potentially interfere with the conduct of the study or confound efficacy evaluations, including the following as specified in numbers 31 through 38 below:
31. Presence of pain, or any masquerading symptoms presenting as neuropathy including central pain, radiculopathy, painful arthritis, etc., that could interfere with the interpretation of the neuropathy endpoint assessments at the discretion of the PI.
32. Major skin or soft-tissue lesions in the dosing from below the knees to the bottom of both feet, and hands), small lesions (i.e., size of coin) are acceptable. However, topical application of study drug to these areas should be avoided.
33. Exposure to an experimental drug, experimental biologic, or experimental medical device within 3 months before screening.
34. Any open wound(s) and/or sunburn(s) in the dosing area. Subjects who have a wound and/or sunburn at screening that is anticipated to resolve before day -1 can be enrolled.
35. History of a serious skin disease (as determined by the Investigator), such as skin cancer, psoriasis, stasis dermatitis or eczema.
36. Receipt of a tattoo in the dosing area within 12 months of dosing.
37. Known or untreated Lyme disease.
38. Any abnormal or clinically significant lab or test result, collected from the Screening or Baseline visits that in the Investigator's opinion would not make the subject an ideal participant in this trial.