# Presentation: 679723

## NDA 21- 174

- Gemtuzumab Ozogamicin in relapsed acute myeloid leukemia
- FDA Review
- ODAC March 17, 2000

**Notes:**
Good morning,  I will be presenting the FDA review of gemtuzumab ozogomycin in relapsed Acute myeloid leukemia.

## Pharmaceutical Category: Immunotoxin

-  Recombinant humanized murine anti- CD-33 antibody (hP67.6) linked to calicheamicin

**Notes:**
Immunotoxins are a novel class of antineoplastic drugs in which a toxin is attached to an antibody against an antigenic epitope found on cancer cells. 

## Gemtuzumab Ozogamicin

- <date/time>

-             Proposed indication:
**“****For the Treatment of CD 33 positive acute myeloid leukemia in relapse” **

**Notes:**
The proposed indication is the treatment of relapsed CD33 positive AML

## Gemtuzumab Ozogamicin

- <date/time>

**Gemtuzumab Ozogamicin**

-             **Proposed indication:**
**“****For the Treatment of CD 33 positive acute myeloid leukemia in relapse”**

**Notes:**
The proposed indication is the treatment of relapsed CD33 positive AML

## Regulatory Issues: Accelerated Approval

- Sponsor needs to demonstrate ‘meaningful therapeutic benefit over existing treatments.’
- In this case, equal efficacy with improved safety.
- Benefit must be based on a surrogate endpoint which is ‘likely to predict clinical benefit’ (Subpart H)

**Notes:**
Regulatory issues:
To achieve accelerated approval,  the sponsor needs to demonstrate meaningful therapeutic benefit over existing treatments.’ 
Although there is currently no drug specifically approved for use in relapsed AML, there areseveral available therapeutic regimens The sponsor needs to demonstrate efficacy comparable to available treatments in addition to demonstrating improved safety.’
In this case complete response is considered a surrogate endpoint.

## Regulatory Issues: Accelerated Approval

- In hematologic malignancies, durable complete remissions have been considered as adequate evidence of clinical benefit.
- Durability was difficult to determine in this application so complete response was considered to be an acceptable surrogate
- Requires Phase 4 post approval study commitments to confirm clinical benefit

**Notes:**
* For hematologic malignancies, durable complete remissions have been considered as adequate evidence of clinical benefit.  In this case, however, the duration of responses is difficult to measure because of subsequent therapies, especially stem cell transplantation. Since duration of  response is difficult to measure response would be viewed as a surrogate for clinical benefit. 
*Accelerated approval regulations require the sponsor to initiate postmarketing studies following approval in order to confirm clinical benefit

## Overview of Review Issues

- Efficacy Issues
- Equivalence of CR’s and CRp’s
- Overall efficacy compared with conventional salvage chemotherapy
- Efficacy in Patient Subgroups
- Interpretation of survival data in absence of  consistent  postremission therapy
- Safety Issues
- Safety advantage
- Hepatotoxicity

**Notes:**
There are several review issues of concern in this application. * Regarding efficacy, * We believe that questions still remain concerning the comparability of  the response categories of complete remission and CRp.  * Is this drug equally as efficacious as conventional salvage chemotherapy regimens?  *Which patients groups  would benefit most? * How do we interpret survival data in the absence of any consistent postremission therapy? *Regarding safety, * How significant is the hepatotoxicity reported with this drug? * Is there really a safety advantage with this drug over conventional leukemia salvage treatments?

## Studies submitted for Reviewas of 10/99

**Notes:**
These were the studies originally submitted for review in October. They included a phase 1 study of 42 patients, and three phase 2 studies totaling 104 patients. (point) Note that the phase 2 studies are still ongoing and continuing to accrue patients. 

## Studies Reviewed

- 41 patients in Phase 1 study
- 104 patients from original NDA
- Updated safety and efficacy data on 142 patients 1/27/00

**Notes:**
* Originally we received data on 41 patients in the phase 1 studies * and 104 patients in the phase 2 studies. *In January we received efficacy and safety updates on the original study patients and * In early February we received updated safety and efficacy data on an additional 38 patients. The trials are still accruing patients.

##  INCLUSION AND EXCLUSION CRITERIA 

-  INCLUSION AND EXCLUSION CRITERIA

**Notes:**
Differences between the studies are highlighted in yellow. Study 202,  allowed patients who relapsed following transplant, however only two such patients were enrolled. (point)  Study 203 allowed older patients with worse prognostic features: worse markers hepatic and renal function, and shorter durations of remission (point)

## Protocol outline

- Single 2 hour infusion 9 mg/M2 given as outpatient and repeated in 14 days
- Eligibility determined at site, CD 33 confirmed by central flow cytometry lab
- Responses determined by central independent pathologist
- Growth Factors not allowed

**Notes:**
The sponsor has already described the protocol in detail.*briefly, the study drug was given as a single 2 hour intravenous infusion which was repeated once on day 14.
  *Eligibility was determined  on site* but responses were determined by  an independent pathologist. * No growth factors were allowed in this protocol.

## Primary Endpoints: SafetyComplete Response (CR)

- CR was defined by all of the following:
- Leukemic blasts absent from peripheral blood;
- Percentage of blasts in the bone marrow _<_ 5%;
- Hemoglobin _>_9 g/dL, platelets _>_ 100,000/μL, absolute neutrophil count _>_ 1500/μL;
- Red blood cell and platelet-transfusion independent

**Notes:**
Primary endpoints: were safety and Complete Response.
* Complete response was defined by conventions commonly used in leukemia trials including: * absence of circulating blasts, * no increased blasts in the marrow,  and * untransfused hematology values as noted.  * Patients had to be transfusion independent of platelets for one week and RBCS for 2 weeks.

## “Morphologic Remission” (CRp)

- CRp defined in the same way as Complete Remission, except that platelets were not required to reach 100,000/μL
- Not a primary endpoint
- Patients required to achieve RBC and platelet transfusion independence

**Notes:**
Morphologic Remission was the term originally coined to describe this group of patients later termed CRp’s. * These remissions were defined in the same way as complete remissions, except that the platelets never recovered. * Remember that CRp was not a primary endpoint and * also that patients had to achieve transfusion independence to be called a CRp.

## “Morphologic Remission” (CRp)

- Patients  never achieve a platelet count of 100K
- Drug Toxicity vs. residual leukemia?
- Preclinical studies
- Megakaryocyte colony suppression *in vitro*
- Gene chip expression
- Long term effects on stem cells *in vivo?*

**Notes:**
In Phase 1 trials, *  a group of patients was identified who had clearance of blasts with incomplete platelet recovery. These were originally referred to as “morphologic remissions,” subsequently the term CRp was coined. 
*  It was postulated that for some reason this group of patients was susceptible to the toxic effects of gemtuzumab ozogomycin on the stem cells megakaryocyte precursars, although persistant leukemia might also  explain the failure of these patients to achieve  normal platelet counts. * in vitro suppression of megakaryocyte colony forming cells was observed in the marrow, obtained from normal donors. Gene chip expression studies failed to find a correllation of remission status with MDR expression. However, long term in vivo effects of gemtuzumab ozogomicin on stem cells are still to be determined.  
 What does this have to do with leukemia treatment? 

## Efficacy Results: original 104 patients with relapsed AML

**Notes:**
Combined efficacy results for the original 104 patients are highlighted in yellow and  showed a 31% combined overall response rate, but only 17% of patients achieved a complete response. (point)  Any claim of efficacy is largely dependent upon the inclusion of the significant subset of patients with a CRp. The results were fairly uniform between the different trials, with patients in study 203 demonstrating somewhat worse response rates which might be  expected in  an older population group. 

## Original NDA  (N=104) compared with updated efficacy data (N=142)

**Notes:**
The updated efficacy results with an additional 38 patients

## Original NDA  (N=104) compared with updated efficacy data (N=142)

**Notes:**
showed a similar overall response rate of about 30% compared with 31% with the original data. The additional data did not appear appreciably to alter the overall response rates, but confirmed the importance of the inclusion of the CRp’s in the efficacy results.

## CRp=CR?Relapse-Free Survival

**Notes:**
 The sponsor has presented data on survival to support their claim that the CR’s are clinically identical to CRp’s. The CRp’s in fact (point) appear to demonstrate a somewhat decreased RFS by our calculations 4.4 mo  compared  with 7.9 mo in the CR patients, however the numbers are far too small to make any definitive conclusions either way. 

## Relapse-Free Survival

**Notes:**
Overall Survival appears similar in our graph of the CR and CRp groups, and both responding  groups clearly do better than the nonresponders. However I would like to emphasize that the numbers are really too small to make any definitive conclusions regarding equivalency

## Survival data Issues

- Small numbers
- Additional antileukemic therapy in 22/32 (70%) of overall responders
- 13/32 responders transplanted
- 6/18 (33%) CR’s (4 Allo)
- 7/14 (50%) CRp’s  (6 Allo)
- Survival data not censored for postremission therapy

**Notes:**
* In addition to the small sample size, a major problem with the interpretation of survival data in this study was * the lack of any consistent postremission therapy. * Patients who were eligible went on to transplant,*  and successful allogeneic transplant is correlated with long term survival in relapsed AML. *  It was not feasible to censor the results for transplant because of the small numbers involved. 

## Prognostic Factors in Relapsed AML

- Age
- Duration of First Remission

**Notes:**
The most important predictors of response in relapsed AML are thought to be *age and *duration of first remission

## Response Rates vs. Age

**Notes:**

Keeping in mind  the inherent hazards of drawing conclusions from historical comparisons, nonprespecified subset analysis, in single arm trials with small numbers of patients, I believe these are all chapters in Dr. Temple’s book on the No no s of clinical trial analysis, but also keep in mind the necessity to provide some specific measure for comparison. Looking at at response rates vs age reported in several studies of salvage regimens for relapsed AML, the references are in the review, and comparing them with the response rates in the GoZ trials. 
.
.

## Response Rates vs. Age

**Notes:**

it looks as if older patients, highlighted here in yellow, did variably well depending on the study but overall appeared to do about as well with the gemtuzumab ozogomicin as with conventional chemotherapy. (point) if you include the CRp’s.
Younger patients receiving gemtuzumab ozogomycin here highlighted in green may have  somewhat lower response rates compared with those reported in the literature with conventional salvage chemotherapy.
.

.

## Response Rates vs. Duration of First Remission 

**Notes:**
If we compare response rates in the literature versus durations of first remission, you will see why this is considered to be a very important prognostic factor. Looking first at patients with shorter durations of first remissions, treated with a variety of salvage regimens,

## Response Rates vs. Duration of First Remission 

**Notes:**
 and presumably worse prognosis, which are highlighted here in yellow (point)  this group appears to have response rates more or less similar to those reported in the literature, if you include the CRp group. . 

However, when we look at response rates reported in  relapsed patients who have enjoyed relatively long durations of first remission,and are thought to be in a more favorable prognostic category,  here highlighted in green, (point) we find that the response rates reported in the G O trials, (point)  are probably quite as high as the results reported generally in the literature.
These observations are exploratory and are meant only to raise questions and  suggest further studies, and was not intended to suggest any definitive conclusions regarding the efficacy of this drug in  different patient subgroups

## Efficacy Conclusions

- Response rate difficult to compare to conventional salvage chemotherapy
- Comparability requires inclusion of CRp’s
- Efficacy in prognostic subgroups requires further study
- Duration of responses are difficult to determine because of wide variety of postremission treatments

**Notes:**
Efficacy conclusions: *
In the absence of randomized trials, comparable efficacy is difficult to determine, this drug may be equal to available therapy in certain patient subgroups but any claim of comparability depends upon inclusion of CRp group in calculation of the response rates. The claim of equivalence is not yet statistically established. 
Efficacy in different prognostic subgroups requires further study
Duration of responses are difficult to determine because of wide variety of postremission treatments. 

## Safety Issues

- Acute infusion-related symptoms
- Antibodies
- Bleeding
- Infections
- GI Toxicity

**Notes:**
The safety review issues I plan to cover include 
* Acute infusion-related symptoms
*Antibodies responses
*Bleeding
*Infections
*And GI toxicity, especially liver toxicity
with attention to VOD of the liver

## Safety: Acute Infusion-Related Events

- Infusion-related symptom complex in 50%
- Fever, chills, usually mild
- Outpatient administration feasible
- Occasional hypotension, hypoxia

**Notes:**
* Acute infusion-related symptoms were common * but appeared to be generally mild and reversible. * Outpatient administration of this drug appears feasible in an infusion clinic equipped to manage the occasional hypotensive or hypoxic episode. 

* No antibodies to the humanized murine monoclonal antibody were detected in any patients by the ELISA assay. *  Two patients developed antibodies to the linker complex in the phase 1 trials, but these patients had received at least 3 doses of the drug. 

## Safety: Antibodies

- No HAHA anti-idiotype antibodies detected in 104 patients in phase 2 trials who received 1,2, or 3 infusions (additional studies requested)
-  2/42 patients in phase 1 trial developed antibodies to linker complex, 1 with transient symptoms

**Notes:**
* Acute infusion-related symptoms were common * but appeared to be generally mild and reversible. * Outpatient administration of this drug appears feasible in an infusion clinic equipped to manage the occasional hypotensive or hypoxic episode. 

* No antibodies to the humanized murine monoclonal antibody were detected in any patients by the ELISA assay. *  Two patients developed antibodies to the linker complex in the phase 1 trials, but these patients had received at least 3 doses of the drug. 

## Safety: Bleeding and Transfusion Events(per person )

**Notes:**
Minor bleeding appeared increased in the CRp grou, here highlighted in yellow, compared with the CR’s highlighted in green. The incidence of major bleeding was too uncommon for statistical analysis and there did not appear to be an increased risk of major bleeding adverse events in the CRp group. Significantly more platelets were transfused in the CRp’s,  compared with the CR’s (point) and a trend towards more Packed Red Blood cell transfusions  was seen in the CRp’s. 
Again more transfusions were needed in the nonresponders than in any of the  responding groups.

## Safety: Bleeding

**Notes:**
Keeping in mind  the inherent hazards of historical controls, but also the necessity to provide some specific measure for comparison, we looked at bleeding risks reported in several recently published studies of salvage regimens for relapsed AML. References are contained in the questions to the Committee. 
It appears that patients treated with gemtuzumab ozogomycin here highlighted in yellow (point) appeared to have a similar risk of grade 3-4 bleeding, and almost half the time to platelet recovery, in comparison with those treated with HIDAC-m (point). Bleeding risk and platelet recovery appear to be similar between GoZ and FLAG (point). In this uncontrolled analysis, the bleeding risk of GOZ appeared to be comparable to or improved compared with other salvage regimens. 

## Safety: Neutropenia, Infections

**Notes:**
Compared with most of the other salvage regimens, recovery from neutropenia was more rapid, and the incidence of severe infections appeared to be markedly reduced  (point). 

## Safety: GI Toxicity

**Notes:**
Nausea, vomiting, and mucositis appeared reduced in those patients receiving GoZ. (point)  However, there appeared to be an increased incidence of liver function abnormalities, in patients treated with GoZ (point) compared with other regimens.

## Safety: Hepatotoxicity

- Calicheamicin (unconjugated) noted to cause liver toxicity in preclinical testing
- 14% grade 3-4 elevations of AST and 24 % grade 3-4 elevations in total bilirubin reported in the phase 2 trials.
- 13 patients exhibited elevations of both transaminases and bilirubin, generally transient and reversible

**Notes:**
Hepatotoxicity: *Unconjugated calichiamicin was noted to be hepatotoxic in preclinical testing. * There were 14% grade 3-4 elevations of AST and 24 % grade 3-4 elevations in total bilirubin reported in the phase 2 trials. * Thirteen patients exhibited elevations of both AST and bilirubin, which is considered a marker for potentially significant liver injury. Most of these were transient and reversible.

## Hepatic Venoocclusive Disease (VOD)

- 4 patients with transient VOD in study
- 2 with prior Hematopoetic Stem Cell Transplant (HSCT)
- 1 patient developed transient VOD, died of  pulmonary embolism

**Notes:**
*One 74 year old male was noted to have jaundice which persisted for several months. Another patient died after developing jaundice several days following treatment, but the cause was attributed to multiorgan failure and sepsis. 
Hepatic venoocclusive disease is a well-known and potentially fatal complication of myeloablative chemotherapy and transplantation. Diagnosis  is clinical, and sometimes difficult  from a reviewers perspective. * One patient developed transient VOD during the study and recovered, tolerating the second dose without problems. 4 patients who went on to allogeneic transplant were died of VOD, although three were nonresponders. and one patient with a history of VOD  who was given goz for a relapse following transplant on a compassionate single patient IND  developed fatal VOD. 

## Hepatic Venoocclusive Disease (VOD)

- 1 patient developed persistent jaundice  and died of hepatic failure 156 days after treatment
- 3 died of VOD following HSCT
- 1/15 (6%) responder
- 2/12 (17%)  nonresponders
- 1 pt. died with VOD after treatment of relapse post-transplant (hx. previous VOD)

**Notes:**
*One 74 year old male was noted to have jaundice which persisted for several months. Another patient died after developing jaundice several days following treatment, but the cause was attributed to multiorgan failure and sepsis. 
Hepatic venoocclusive disease is a well-known and potentially fatal complication of myeloablative chemotherapy and transplantation. Diagnosis  is clinical, and sometimes difficult  from a reviewers perspective. * One patient developed transient VOD during the study and recovered, tolerating the second dose without problems. 4 patients who went on to allogeneic transplant were died of VOD, although three were nonresponders. and one patient with a history of VOD  who was given goz for a relapse following transplant on a compassionate single patient IND  developed fatal VOD. 

## Safety Summary: Advantages

- Outpatient administration feasible
- Antibodies uncommon
- Severe infection, mucositis probably  reduced

**Notes:**
In summary, * gemtuzumab ozogomicin appears to have modest safety advantages compared with literature conventional salvage regimens
* Outpatient administration appears feasible, 
Reduced incidence of severe mucositis and severe infection
Myelotoxicity appeared similar however several patients who received more than two doses suffered prolonged aplasia. 

## Safety Summary: Disadvantages

- Markers for hepatotoxicity
- Grade 3-4 elevation in bilirubin in 24%
- Grade 3-4 elevations in AST in 14%
- Both elevated in 13%
- Generally reversible
- Rare persistent jaundice
-  VOD especially in HSCT setting

**Notes:**
In comparison with literature reports of conventional salvage regimens for relapsed AML, gemtuzumab ozogomicin appears to have
* increased risk of * elevated bilirubin and * transaminases or * both  which is can be a marker for potential hepatotoxicity. Abnormalities are *generally reversible, however there was * one patient with persistent jaundice and  some* risk of  VOD especially in BMT setting.  

## Issues to Consider

- Is efficacy equivalent to conventional salvage regimens?
- Is there adequate demonstration of improved safety especially prior to transplant?
- Which patient populations might benefit?
- Elderly?
- Poor prognosis groups?
- Those awaiting transplant?

**Notes:**
Some issues to consider: 
* Is efficacy really equivalent to conventional salvage regimens? The results of this trial are difficult to compare with those of conventional salvage chemotherapy but in any case comparable efficacy would rely on the inclusion of the CRp’s.
*Is there adequate demonstration of improved safety to warrant accelerated approval especially in those patients who will go on to transplant?
* Which patient populations might benefit from this drug? 
* Elderly?
* Poor prognosis groups?
*As a temporizing measure for patients awaiting allogeneic match?

## Regulatory Options:

- Approval based on current interim data with phase 4 commitment to finish studies
- Approval for limited  indications
- Require completion of ongoing studies and resubmission of NDA application
- Require randomized clinical trials and resubmission

**Notes:**
There are three main regulatory options for the Committee to consider:
*The committee could decide to recommend accelerated Approval now based on current interim data with phase 4 commitment to finish current ongoing studies. *The committee could also recommend approval with restricted  indications for this drug.
*Alternatively, the committee could require completion of ongoing phase 2 studies and resubmission of the NDA application when the studies are finished.
* A third option would be to require the completion of randomized clinical trials and resubmission of the NDA at the time of the completion of randomized  studies. 

## Review Team

**Notes:**
I would like to thank the members of my review team ...