# Presentation: 027764

## Abraxane®for the adjuvant treatment of node-positive breast cancer

**Oncologic Drugs Advisory Committee Meeting**
**September 7, 2006**

## Purpose of the Meeting

**To determine if, under the 505(b)(2) pathway, an ****efficacy**** trial in the adjuvant treatment of node-positive breast cancer is required to approve Abraxane in this setting**

## 505(b)(2) Regulatory Pathway

**505(b)(2) Regulatory Pathway**

**505(b)(1): ‘Typical’ way most new drugs are approved;  all investigations from sponsor**
**505(b)(2): Used for new formulations of existing drugs;  applicant may rely on investigations to which it does not own or have the right of reference (e.g. information in the published literature or in approved NDAs for the RLD) **
**505(j): For generic drugs that are the same as the established drug (the ‘Reference Listed Drug’ [RLD])**

## FDA Position Regarding 505(b)(2) 

**“****FDA’s longstanding interpretation of section 505(b)(2) ......... the Agency’s approach is to use the 505(b)(2) drug approval pathway *****to avoid***** requiring drug sponsors to conduct and submit *****studies that are not scientifically necessary*****.”**
**“****The conduct and review of *****duplicative studies***** would ....**** *****slow the process for drug approval***** with no corresponding benefit to the public health.”**

**Source:  Woodcock 2003 Response to Citizen’s Petition regarding 505(b)(2)**

## 505(b)(2) Avoids Significant Delays inDrug Approval

**‘****FDA has approved more than ****80**** section 505(b)(2) applications for drugs for indications ranging from cancer pain to attention deficit disorder. Many of these drugs would never have reached the market, or would have been significantly delayed, without the 505(b)(2) pathway.’**

**Source:  Woodcock 2003 Response to Citizen’s Petition regarding 505(b)(2)**

## Unique Set of Circumstances for Abraxane

**Active ingredient, paclitaxel, is identical **
**Paclitaxel already approved as Adjuvant Rx****(Taxol 175 mg/m****2****)**
**Abraxane delivers a higher dose of paclitaxel****(260 mg/m****2****)**
**Superior anti-tumor activity demonstrated in metastatic breast cancer**
**Tolerability of higher Abraxane dose comparable to lower Taxol dose **
**Abraxane was approved in metastatic breast cancer under 505(b)(2)**
**FDA approach is to use 505(b)(2) *****“to avoid.... studies that are not scientifically necessary”***

## Position of Abraxis BioScience

**Abraxis believes that an *****efficacy***** ****trial in the adjuvant treatment of breast cancer is ‘not scientifically necessary’ and ‘would significantly delay’ the approval of a Cremophor-free paclitaxel alternative**
**Abraxis is committed to conduct a comparative safety trial of Abraxane vs Taxol for women with node-positive breast cancer**

## Reasons that an Efficacy Adjuvant Trial Should not be Required for Approval of Abraxane

**Removing Cremophor Allows Safe Delivery of Higher Doses of Paclitaxel**

**In Metastatic Breast Cancer Abraxane has Greater **
**Anti-tumor Activity****than Taxol**

**Paclitaxel is Approved for****Adjuvant Use (Taxol) **

**The Abraxane Dose of Paclitaxel is Safe and Higher than that Already Proven Effective in the Adjuvant Setting  **

**Reasons that an Efficacy Adjuvant Trial ****Should not be Required for Approval of Abraxane**

***Therefore, there is no scientific basis to hypothesize that Abraxane will be less effective than Taxol as adjuvant therapy***

## Reasons that an Efficacy Adjuvant Trial Should not be Required for Approval of Abraxane

**William J. Gradishar, MD**

**Michael J. Hawkins, MD**

**Clifford A. Hudis, MD**

**Abraxane is Cremophor-free Formulation of Paclitaxel**

**Removing Cremophor Allows Safe Delivery of Higher Doses of Paclitaxel**

**In Metastatic Breast Cancer Abraxane has Greater **
**Anti-tumor Activity****than Taxol**

**Paclitaxel is Approved for****Adjuvant Use (Taxol) **

**The Abraxane Dose of Paclitaxel is Safe and Higher than that Already Proven Effective in the Adjuvant Setting  **

## Development of Paclitaxel Formulations:Historical Background 

**Paclitaxel, one of the most active cytotoxic agents**
**Cremophor****®**** required at high concentrations (Taxol****®**** and generic equivalents)**
**In the 1990’s, Abraxis developed a paclitaxel formulation that replaced Cremophor with Albumin (Abraxane****®****)**
**Preclinical studies subsequently demonstrated that Abraxane significantly improved the therapeutic index of paclitaxel with**
**Less toxicity due to removal of Cremophor**
**Higher paclitaxel dose**
**Higher intra-tumoral paclitaxel concentration**
**Higher efficacy in multiple tumor types**

## 2001: FDA agreed that Abraxane could receive approval in MBC (same indication as Taxol) provided two issues were satisfied:
That replacement of Cremophor with albumin did not result in a decrease in efficacy of paclitaxel
That the higher dose 260 mg/m2 of Abraxane could be administered with comparable tolerability to Taxol at175 mg/m2 

2004: Randomized Phase 3 Trial proved superior anti-tumor activity of Abraxane with comparable tolerability at higherdose than Taxol

2005: FDA granted approval for metastatic breast cancerunder the 505(b)(2) regulatory pathway for new formulationsof existing drugs

**That replacement of Cremophor with albumin did not result in a decrease in efficacy of paclitaxel**
**That the higher dose 260 mg/m****2**** of Abraxane could be administered with comparable tolerability to Taxol at****175 mg/m****2 **
**2004: Randomized Phase 3 Trial proved superior anti-tumor activity of Abraxane with comparable tolerability at higher****dose than Taxol**
**2005: FDA granted approval for metastatic breast cancer****under the 505(b)(2) regulatory pathway for new formulations****of existing drugs**

**Basis of FDA Approval of Abraxane for ****Metastatic Breast Cancer**

## Reasons that an Efficacy Adjuvant Trial Should not be Required for Approval of Abraxane

***Therefore, there is no scientific basis to hypothesize that Abraxane will be less effective than Taxol as adjuvant therapy***

**Abraxane is Cremophor-free Formulation of Paclitaxel**

**Removing Cremophor Allows Safe Delivery of Higher Doses of Paclitaxel**

**In Metastatic Breast Cancer Abraxane has Greater **
**Anti-tumor Activity****than Taxol**

**Paclitaxel is Approved for****Adjuvant Use (Taxol) **

**The Abraxane Dose of Paclitaxel is Safe and Higher than that Already Proven Effective in the Adjuvant Setting  **

## Abraxane is Albumin-bound Cremophor-free Paclitaxel

**Abraxane is Albumin-bound ****Cremophor-free Paclitaxel**

**Paclitaxel**

**Albumin**

**Mean = 130 nm**

**cryo-TEM**

**Concentration dependent dissociation into individual paclitaxel-bound albumin molecules**

**Paclitaxel exists in the albumin particle **
**in an non-crystalline, amorphous  state**

## The Active Ingredient in Abraxane and Taxol is Identical

**The Active Ingredient in ****Abraxane and Taxol is Identical**

**Supplied As**
- Paclitaxel 6 mg/ml
**Cremophor 537 mg/ml**
**Ethanol 396 mg/ml**

**Reconstituted**
- Paclitaxel 5 mg/ml
- Albumin ~45 mg/ml
**No Solvents**

**Abraxane is a Cremophor-free**
**Formulation of Paclitaxel**
**Received  FDA **
**Approval **
**January, 2005**
**for metastatic  breast cancer**

## Abraxane was Developed to Eliminate Cremophor-induced Hypersensitivity Reactions

**Taxol Package Insert**

***“******Anaphylaxis and severe hypersensitivity reactions...have occurred in 2-4% of patients receiving Taxol in clinical trials”***

***“******Fatal reactions have occurred in patients despite premedication”***

**Hyperglycemia **
**Glucose intolerance in diabetics**
**Mood changes**
**Insomnia**

**Common Steroid Side Effects when Given as Premedication**

## Abraxane was Developed to Eliminate Cremophor-induced Hypersensitivity Reactions

**Taxol Package Insert**

***“******Anaphylaxis and severe hypersensitivity reactions...have occurred in 2-4% of patients receiving Taxol in clinical trials”***

**Abraxane Package Insert**

***“******No premedication to prevent hypersensitivity reactions is required prior to administration of Abraxane”***

***“******Fatal reactions have occurred in patients despite premedication”***

## Removal of Cremophor Results in Different PK for Taxol and Abraxane

**Abraxane is Cremophor-free Formulation of Paclitaxel**

**PK linearity**
**Alterations in distribution phase**

## Cremophor Entraps Paclitaxel in Micelles in the Plasma Compartment 

**Cremophor Entraps Paclitaxel in Micelles in the Plasma Compartment **

**	****Control plasma****	****Plasma + Taxol**

**Cremophor****Micelle**

**Sparreboom A et al. Cancer Research, 1999;59:1454–1457.**
**van Tellingen O et al:  British Journal of Cancer, 1999; 81:330-35.**

**Paclitaxel is entrapped in Cremophor micelles**
**This results in non-linear paclitaxel PK for Taxol**

## Paclitaxel PK for Abraxane are Linear

**(1): Kearns, C. M., Pharmacotherapy, 1997**
**(2): Taxol Package insert**
**(3): Mross et al, Cancer Chemother Pharm 2000**

**Taxol**

**Abraxane**

**Source:  Abraxane NDA**

## Cremophor Alters the Distribution PhasePK of Paclitaxel

**Source: Abraxane NDA and Sparreboom et al., 2005, CCR**

## Reasons that an Efficacy Adjuvant Trial Should not be Required for Approval of Abraxane

***Therefore, there is no scientific basis to hypothesize that Abraxane will be less effective than Taxol as adjuvant therapy***

**Abraxane is Cremophor-free Formulation of Paclitaxel**

**Removing Cremophor Allows Safe Delivery of Higher Doses of Paclitaxel**

**In Metastatic Breast Cancer Abraxane has Greater **
**Anti-tumor Activity****than Taxol**

**Paclitaxel is Approved for****Adjuvant Use (Taxol) **

**The Abraxane Dose of Paclitaxel is Safe and Higher than that Already Proven Effective in the Adjuvant Setting  **

## Reasons that an Efficacy Adjuvant Trial Should not be Required for Approval of Abraxane

**260 mg/m****2**** Q3W:**
**Phase 3 MBC**

**260 mg/m****2**** Q2W:**
**Adjuvant setting**

***Therefore, there is no scientific basis to hypothesize that Abraxane will be less effective than Taxol as adjuvant therapy***

**Abraxane is Cremophor-free Formulation of Paclitaxel**

**Removing Cremophor Allows Safe Delivery of Higher Doses of Paclitaxel**

## Abraxane can Deliver Higher Paclitaxel Dosewith Comparable Tolerability to Taxol

| CA012 Randomized Phase 3 Trial in Metastatic Breast Cancer | Abraxane
260 mg/m2n = 229 | Taxol
175 mg/m2 n = 225 |
| --- | --- | --- |

**The tolerability of Abraxane was equivalent to that of Taxol at a 50% higher DELIVERED dose.**

|  |  |  |
| --- | --- | --- |
| Median cycles/patient | 6 | 5 |
| Percentage of planned dose | 98% | 98% |
| Mean paclitaxel dose intensity q3w | 255 mg/m2 | 171 mg/m2 |

## Abraxane and Taxol have Comparable Overall Toxicity Profiles

**Percentage of Patients**

**All Cycles**

**Abraxane 260 mg/m****2****	****Taxol 175 mg/m****2****n = 229****	****n = 225**

**After 4 Cycles**

## Tolerable GI Toxicities for Abraxane and Taxol

| Adverse Event | Drug | Percentage of Patients by Grade |  |  |  | P-value* |
| --- | --- | --- | --- | --- | --- | --- |
|  |  | 1 | 2 | 3 | 4 |  |
| Nausea | Taxol | 12 | 8 | <1 | 0 | 0.039 |
|  | Abraxane | 19 | 7 | 3 | 0 |  |
| Vomiting | Taxol | 4 | 4 | 1 | 0 | 0.022 |
|  | Abraxane | 10 | 4 | 3 | <1 |  |
| Diarrhea | Taxol | 11 | 3 | 1 | 0 | 0.006 |
|  | Abraxane | 17 | 9 | <1 | 0 |  |

*** Cochran-Mantel-Haenszel test**

## Taxane and Cremophor Related Toxicities

| Adverse Event | Drug | Percentage of Patients by Grade |  |  |  | P-value* |
| --- | --- | --- | --- | --- | --- | --- |
|  |  | 1 | 2 | 3 | 4 |  |
| Neutropenia | Taxol | 10 | 19 | 32 | 22 | < 0.001 |
|  | Abraxane | 21 | 25 | 32 | 9 |  |
| Hypersensitivity Reactions | Taxol | 8 | 3 | 2 | 0 | 0.001 |
|  | Abraxane | 3 | <1 | 0 | 0 |  |
| Peripheral Neuropathy | Taxol | 43 | 10 | 2 | 0 | < 0.001 |
|  | Abraxane | 41 | 20 | 10 | 0 |  |

*** Cochran-Mantel-Haenszel test**

## Improvement from Grade 3 Sensory Neuropathy and Resumption of Treatment with Abraxane (n = 24)

**0.75**
**0.50**
**0.25**
**0.00**

**Days since grade 3 to improvement**

**Median = 22 days**

**0****	****10****	****20****	****30****	****40****	****50****	****60****	****70****	****80****	****90****	****100****	****110****	****120****	****130****	**

**Proportion not resolved**

- *

- *

- *

- *

**Improvement from Grade 3 Sensory Neuropathy and Resumption of Treatment with Abraxane (n = 24)**

**Source: Abraxane NDA.***** Censored (n = 10 patients)**

***10/14 patients resumed Abraxane at a lower dose***

## Reasons that an Efficacy Adjuvant Trial Should not be Required for Approval of Abraxane

***Therefore, there is no scientific basis to hypothesize that Abraxane will be less effective than Taxol as adjuvant therapy***

**Abraxane is Cremophor-free Formulation of Paclitaxel**

**Removing Cremophor Allows Safe Delivery of Higher Doses of Paclitaxel**

**260 mg/m****2**** Q3W:**
**Phase 3 MBC**

**260 mg/m****2**** Q2W:**
**Adjuvant setting**

## Results of a Pilot Adjuvant Trial of Dose Dense Abraxane

**CA030: U.S. Oncology (P.I. Nicholas Robert)**
**Dose Dense AC x 4 → Abraxane x 4 (all cycles q2w)**
**Abraxane dose 260 mg/m****2**
**30 received AC; 29 received Abraxane**
**27/29 (93%) received all 4 Abraxane cycles**
**Comparable to Taxol q 3 weeks**
**Mean cumulative dose 962 mg/m****2**** **
**Well tolerated without unexpected toxicity**
**Peripheral neuropathy prospectively monitored and followed to resolution**
**28/29 (97%) patients asymptomatic 8 months following treatment**

## 28/29 (97%) Patients were Asymptomatic* fromPeripheral Neuropathy within 8 Months Following Dose Dense Abraxane at 260 mg/m2

**28/29 (97%) Patients were Asymptomatic* from****Peripheral Neuropathy within 8 Months Following Dose Dense Abraxane at 260 mg/m****2**

*** Grade 0 or 1 per NCI CT CAE**

**Proportion Asymptomatic***

**Months**

**59% asymptomatic at end of 4 cycle RX**
**75% 2 months p Rx**
**97% 8 months p Rx**

## Ongoing Adjuvant Safety Trials

| Institution | P.I. | Design | N |
| --- | --- | --- | --- |
| US Oncology | JohnPippen | dd AC x 4 cycles→dd Taxol or Abraxane x 4 cyclesRandomized, with Bevacizumab | N = 4 of 200 (Accrual ongoing) |
| Dana Farber (DFCI) | Harold Burstein | dd AC x 4→ 
dd Abraxane 260 mg/m2 x 4 | N = 39 of 50(Accrual ongoing) |
| MSKCC and UCSF | Maura Dickler and Hope Rugo | dd AC x 4 + Bevacizumab →dd Abraxane 260 mg/m2 x 4 + Bevacizumab→ Bevacizumab | N = 12 of 75(Accrual ongoing) |
| University of Washington | Georgiana Ellis | Wkly Doxorubicin + oral Cy→Wkly Abraxane 100 mg/m2 x 12 +/- Trastuzumab | N = 1 of 60(Accrual ongoing) |
| NSABP* | André Robidoux | ABX 100 mg/m2 wkly x12→FEC x 4 +/- Trastuzumab→ surgery | N = 67 of 67(Accrual completed) |

## Design of Proposed Comparative Safety Study using the Approved Dosing Schedules of Abraxane and Taxol

**AC **
**x 4 cycles**

**Taxol 175 mg/m****2****IV over 3 hrs q 3 wk**
**Standard Premedication with Dexamethasone and Anti-histamines**

**Abraxane 260 mg/m****2**** ****IV over 30 min q 3 wk**
**No Standard Premedication**

**Randomization **

**x 4 cycles**

**Final design to be agreed upon with FDA**

**Objective:  ****	**
**Describe safety profiles of Abraxane and Taxol in Adjuvant Breast Cancer following AC x 4**

## How Similar or Dissimilar are Taxol and Abraxane?

**The active ingredient in both formulations is paclitaxel**
** ****Administration Differences**
**Cremophor-related HSRs are eliminated with Abraxane**
**No steroid premedication required with Abraxane**
**Standard IV tubing with shorter infusion time**
**Differences in PK due to paclitaxel sequestration by Cremophor **
**The removal of Cremophor permits delivery of a 50% higher dose of paclitaxel than that of Taxol**
**Despite higher dose the tolerability of Abraxane is comparable to that of Taxol**
**Abraxane demonstrated higher anti-tumor activity than Taxol in metastatic breast cancer**

## Reasons that an Efficacy Adjuvant Trial Should not be Required for Approval of Abraxane

***Therefore, there is no scientific basis to hypothesize that Abraxane will be less effective than Taxol as adjuvant therapy***

**Abraxane is Cremophor-free Formulation of Paclitaxel**

**Removing Cremophor Allows Safe Delivery of Higher Doses of Paclitaxel**

**In Metastatic Breast Cancer Abraxane has Greater **
**Anti-tumor Activity****than Taxol**

**Paclitaxel is Approved for****Adjuvant Use (Taxol) **

**The Abraxane Dose of Paclitaxel is Safe and Higher than that Already Proven Effective in the Adjuvant Setting  **