gilvetmab

For Use in Dogs Only

Conditionally licensed. For use by a veterinarian only.

IN THE ABSENCE OF A VETERINARIAN-CLIENT-PATIENT RELATIONSHIP, FEDERAL REGULATIONS PROHIBIT THE RELABELING, REPACKAGING, RESALE OR REDISTRIBUTION OF THE INDIVIDUAL CONTENTS OF THIS PACKAGE.

This product contains gilvetmab, a caninized monoclonal antibody against canine programmed cell death receptor-1. For the treatment of dogs with mast cell tumors or melanomas. This product has demonstrated a reasonable expectation of efficacy and a preliminary safety profile in reducing the solid tumor burden in dogs with stage I, II, and III mast cell tumors or dogs with stage II and III melanomas. This product license is Conditional; safety, efficacy, and potency have not been fully evaluated. For more information regarding safety, see productdata.aphis.usda.gov.

This monoclonal antibody remains in the circulation for several weeks. It exerts its effect by binding to its target receptor on canine CD4+ and CD8+ T lymphocytes. Like other naturally-occurring antibodies, elimination is via normal protein degradation pathways.

Directions For Use

Administer gilvetmab as an intravenous (IV) infusion of 4.5 mg/lb or 0.225 mL/lb (10 mg/kg or 0.5 mL/kg) body weight over at least 30 minutes. Administer manually or use a constant rate syringe pump. Repeat administration every 2 weeks for up to 10 treatments. Discuss with your veterinarian or the manufacturer if treatment is required beyond 10 treatments. Antihistamine (diphenhydramine 2 mg/kg) premedication orally (PO) 4 hours before or intramuscularly (IM) 15-30 minutes before is recommended prior to each treatment to prevent or reduce the severity of infusion-related reactions.

EFFICACY

The clinical efficacy and safety of this antibody was evaluated in client-owned dogs with naturally-occurring mast cell tumors (stages I-III) or melanomas (stages II-III). The study was a single arm, open-label, multicenter investigation involving nine clinics in the United States. The antibody was administered to dogs by intravenous (IV) infusion over a minimum of 30 minutes and the dogs were monitored for 6 hours post treatment for adverse events (AE). The study examined objective responses (changes in tumor size) that were evaluated following the canine Response Evaluation Criteria in Solid Tumors (cRECIST v1.0). Briefly, the longest diameters of between 1 and 5 target lesions were evaluated every 28 days and the sum of the longest diameters was calculated. Responses were classified as:

Complete Response (CR): disappearance of all target lesions.

Partial Response (PR): at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease (PD), taking as reference the smallest sum diameters while on study.

Progressive Disease (PD): either the appearance of one or more new lesions or at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum diameters while on study.

Non-Evaluable (NE): a dog enrolled and treated in the study with stable disease that is lost to follow up before the minimum time of follow up evaluation.

Results were reported as best overall response for each dog at any single time period and the objective response was classified as yes (if either a CR or PR) or no (if either SD or PD).

Mast cell tumors: As indicated in Table 1, a total of 26 dogs with stage I, II, or III tumors were treated with up to a maximum of 12.7 mg/kg antibody every 14 days for up to 10 doses. A total of 12 dogs (46%) had an objective response with 2 dogs having a complete response and 10 dogs having a partial response. A total of 7 dogs (27%) had stable disease and 6 dogs (23%) had progressive disease.

Melanomas: As indicated in Table 2, a total of 25 dogs with stage II or III tumors were treated with up to a maximum of 12.7 mg/kg antibody every 14 days for up to 10 doses. A total of 5 dogs (20%) had an objective response with 2 dogs having a complete response and 3 dogs having a partial response. A total of 10 dogs (40%) had stable disease and 8 dogs (32%) had progressive disease.

The combined complete and partial response rate with 95% confidence interval for both tumor types are summarized in Table 3.

Dogs which had previous cancer therapies administered prior to treatment with this product are summarized in Table 4.

Table 1. Efficacy for Mast Cell Tumors

¹CR=complete response; ²PR=partial response; ³SD=stable disease; ⁴PD=progressive disease; ⁵NE=non-evaluable

Table 2. Efficacy for Melanomas

¹CR=complete response; ²PR=partial response; ³SD=stable disease; ⁴PD=progressive disease; ⁵NE=non-evaluable

Table 3. Objective Response Rates for All Tumor Types

*Calculated by Clopper-Pearson method, which ignores factors such as cancer stage, breed, site, etc. For this reason, it is likely that the width of the confidence intervals is underestimated.

Table 4. Prior Cancer Therapy

*Dogs could have received prior cancer treatment in more than one therapy category.

SAFETY

The antibody has been demonstrated to be well-tolerated in dogs in a laboratory safety study, in which 50 beagle dogs were treated with the antibody at 6 mg/kg every 21 days for 5 IV infusions and compared against 10 dogs treated with a placebo for 5 IV infusions. There were no treatment-related adverse events observed during the study with the exception of three dogs, which displayed mild to moderate clinical signs consistent with an allergic reaction. All clinical signs resolved rapidly with treatment. These clinical signs reoccurred in one dog on the next treatment while the other 2 dogs did not display these clinical signs again on subsequent treatments.

A field study demonstrated that this antibody is well tolerated in client-owned dogs with mast cell tumors or melanomas after IV infusion over at least 30 minutes. A total of 51 dogs enrolled in the study were evaluated for adverse events (AE). Dogs maintained a favorable quality of life as indicated during the study by >92% of owners of melanoma patients and 100% of owners of mast cell tumor patients.

The following tables present the most common or consequential adverse reactions (AR) that were reasonably associated with the use of this product. For more complete information regarding safety, see productdata.aphis.usda.gov.

Adverse Reactions in Mast Cell Tumor Patients

The following adverse reactions were observed in 26 dogs with naturally occurring mast cell tumors enrolled in the study. The table lists the reactions that were reasonably associated with the use of this product. It does not necessarily indicate the probable cause of the adverse reaction listed. The underlying cause of each individual adverse reaction listed is often uncertain, and may have been caused by the treatment, pre-existing disease, or a combination of treatment and pre-existing disease. Three dogs had a serious AR consisting of anaphylaxis, hypotension, or tumor hemorrhage which resulted in the withdrawal of two of the dogs from the study. There were no grade 5 AR (deaths) that were likely or definitively caused by the product during this study.

Summary of Adverse Reactions related to Mast Cell Tumor Patients

Total number of animals: 26

*Adverse reaction reflects the ‘specify’ per the Veterinary Cooperative Oncology Group (VCOG). ‘Other (specify)’ under the body system category using the most appropriate AR term from other coding dictionaries.

Only the worst grade of an adverse reaction in any given dog is included in the occurrence calculation.

ARs were described and graded following the VCOG consensus document on common terminology for adverse reactions following chemotherapy or biologic antineoplastic therapy in dogs and cats. ¹Grade 1 and 2 ARs are considered mild to moderate with no or outpatient intervention required. Grade 3-5 ARs are severe to life threatening. Grade 5 AR results in death. Adverse reactions that occur in ≥5% of all the dogs in the study or with grade 3 to 5 are included.

¹VCOG, 2016, Veterinary and Comparative Oncology 4: 417-446.

Adverse Reactions in Melanoma Patients

The following adverse reactions were observed in 25 dogs with naturally occurring melanoma enrolled in the study. The table lists the reactions that were reasonably associated with the use of this product. It does not necessarily indicate the probable cause of the adverse reaction listed. The underlying cause of each individual adverse reaction listed is often uncertain, and may have been caused by the treatment, pre-existing disease, or a combination of treatment and pre-existing disease. There were no serious or grade 5 AR (deaths) that were likely or definitively caused by the product within this study.

Summary of Adverse Reactions related to Melanoma Patients

Total number of animals: 25

* Adverse reaction reflects the ‘specify’ per Veterinary Cooperative Oncology Group (VCOG). ‘Other (specify)’ under the body system category using the most appropriate AR term from other coding dictionaries.

Only the worst grade of an adverse reaction in any given dog is included in the occurrence calculation.

ARs were described and graded following the VCOG consensus document on common terminology for adverse reactions. ¹Grade 1 and 2 ARs are considered mild to moderate with no or outpatient intervention required. Grade 3-5 ARs are severe to life threatening. Grade 5 AR results in death. Adverse reactions that occur in ≥5% of all the dogs in the study or with grade 3 to 5 are included.

¹VCOG, 2016, Veterinary and Comparative Oncology 4: 417-446.

PRECAUTIONS

1. Each vial is for single use only and any unused product should be discarded.

2. This product is intended for intravenous use only.

3. Store upright at 2 - 8°C (35 - 46°F). Do not freeze.

4. Do not mix with other products.

5. This product has not been tested in lactating, breeding or pregnant animals.

6. The use of a biological product may produce anaphylaxis. Treat immediately: Epinephrine, corticosteroids, and antihistamines may all be indicated depending on the nature and severity of the reaction.

7. For severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions, stop infusion and permanently discontinue treatment with this product.

8. Contains gentamicin as a preservative.

WARNINGS

Not for use in humans. In case of human exposure, contact a physician.

To report suspected adverse events, contact Merck Animal Health at 1-800-224-5318.

Intervet Inc. d/b/a Merck Animal Health, Omaha, NE 68103 USA

VLN 165A/PCN 9790.02

1 800 224-5318 (USA)

For patent information:

http://www.merck.com/product/patent/home.html

168495-01

CPN: 1047586.0