# Presentation: 523865

## KepivanceTM (Palifermin) Basis for Approval and Pediatric Studies

- KepivanceTM (Amgen)
- Approved 12/15/04
- Joseph E. Gootenberg, M.D.
- Office of Oncology Drug Products
- Division of Biological Oncology Products
- Food and Drug Administration

## KepivanceTM (Palifermin) Keratinocyte Growth Factor

- KepivanceTM (Palifermin) is a recombinant human Keratinocyte Growth Factor (KGF) manufactured in E. coli.
- Endogenous KGF is a member of the fibroblast growth factor family that binds to the unique KGF receptor and stimulates proliferation of epithelial cells.

## KGF Receptor

- The KGF receptor is expressed on epithelial cells.
- Found in many tissues including the gastrointestinal tract (for example tongue, buccal mucosa, salivary gland) and skin.

## Mechanism of Action

- 	KepivanceTM reduces chemotherapy and radiotherapy-induced injury to epithelium by increasing epithelial thickness and enhancing recovery after injury.

## Major Study Supporting Approval

- Randomized placebo-controlled trial comparing KepivanceTM to placebo in patients with hematologic malignancies undergoing  autologous Hematopoietic Stem Cell Transplant
- Primary endpoint: duration of severe oral mucositis
- 212 patients randomized 1:1 to KepivanceTM versus placebo

## Study Population

- Diagnoses – Hematologic malignancies (Non-Hodgkin Lymphoma, Hodgkin Disease, Leukemia, Multiple Myeloma )
- Age 18 to 69 years
- Autologous Peripheral Blood Stem Cell Transplant utilizing a uniform preparative regimen of TBI / VP-16 / Cy and post transplant G-CSF

## Study 1 Trial Schema

## Results of Pre-specified Oral Mucositis Endpoints

| Endpoint | Placebo | KepivanceTM | Statistical Significance |
| --- | --- | --- | --- |
| Mean Duration Grade 3 or 4 Mucositis (Days) | 10.4 | 3.7 | p < 0.001 |
| Incidence Grade 4 Mucositis | 62.2%  | 19.8%  | p < 0.001  |

| WHO Grade | 1 | 2 | 3 | 4 |
| --- | --- | --- | --- | --- |
| Oral Toxicity	  | Soreness and erythema  | Erythema, ulcers
Can swallow solid diet  | Ulcers, extensive erythema 
Cannot swallow solid diet  | Mucositis to the extent that alimentation is not possible  |

##  Label: Indication and Usage

*   *KepivanceTM is indicated to decrease the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support.
-    The safety and efficacy of KepivanceTM have not been established in patients with non-hematologic malignancies.

## Pediatric Aspects of Label

**Special Populations**** **
- 	The pharmacokinetic profile in pediatric  populations (see **PRECAUTIONS: Pediatric Use**) has not been assessed.
**Pediatric Use **
-    The safety and effectiveness of KepivanceTM in pediatric patients have not been established.

## Pharmacokinetics

- _PK Data Available Only In Adults:_

- Mechanism of elimination not known
- Possibly receptor binding and internalization
- Terminal half-life 4.5 hours
- No accumulation with 3 daily doses
- Renal impairment: Insignificant influence on PK

## Safety

- 	The KepivanceTM Transplant Safety Pool included 650 patients (all adults):
- 	409 KepivanceTM and 241 placebo
- 	Most adverse events were attributable to the underlying malignancy, cytotoxic chemotherapy, or TBI and occurred at similar rates in patients receiving KepivanceTM and those receiving placebo.

## Safety

- 	Most of the KepivanceTM related adverse events were consistent with the known pharmacologic action of KepivanceTM on skin and oral epithelium (for example: skin rash, pruritus, erythema, or edema; mouth and tongue thickness or discoloration; and taste disorders).

## PREA Goals for Pediatric Trial 

- Major focus: Safety evaluation
- Determine pharmacokinetics in pediatric age groups likely to be treated with KepivanceTM
- Evaluation of pharmacodynamic effect (reduction in oral mucositis)

## Anti-cancer regimen associated with a high incidence of severe mucositis.

To increase ability to characterize KepivanceTM related adverse events: 
Randomized trial
Uniform underlying disease, clinical status and treatment

- To increase ability to characterize KepivanceTM related adverse events:
- Randomized trial
- Uniform underlying disease, clinical status and treatment

**FDA Considerations: Pediatric Trial**

## FDA Considerations: Pediatric Trial 

- Avoid allogeneic hematopoietic stem cell transplant regimens: high levels of baseline toxicity could confound detection and analysis of KepivanceTM related toxicity.
- Tumor stimulation in cancers of epithelial origin of concern in adult oncology patients is less an issue in pediatric malignancies

## Amgen KepivanceTM InitialPost Marketing Commitment

- Stages 1 and 2  B-cell NHL
- Children  age 3 to 16
- Multi-center dose escalation study
- Placebo controlled
- Evaluate safety, pharmacokinetics, and efficacy of KepivanceTM
- 174 pediatric patients