Phase II Hedgehog Inhibitor for Myelodysplastic Syndrome (MDS)
Study Details
Study Description
Brief Summary
This study is being done to see how safe an investigational drug is and test how well it will work to help people with refractory/relapsed myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML).
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
Phase 2 |
Detailed Description
The main purpose of this study is to see whether the participant's disease responds favorably to the investigational drug, PF-04449913.
Post treatment Phase: After coming off of active treatment study drug (PF-04449913), participants will be followed monthly for survival only. No other data will be captured during this time.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: PF-04449913 Treatment Treatment will be administered on an outpatient basis. All patients will be treated with an oral dose PF-04449913 at 100 mg daily in 4-week cycles for a total of 4 cycles. Patients who demonstrate no evidence of progressive disease (i.e. stable disease or better) may continue on treatment until disease progression or loss of response, limiting toxicity, or death. |
Drug: PF-04449913
Patients will be enrolled according to a two-step study design. Twenty patients will be enrolled in the first stage. All patients will be given a daily oral dose of PF-0444913 100 mg for up to 4 cycles, with an optional continuation phase. Dose escalation to 200 mg will be provided for patients who do not have at least hematologic improvement following 2 cycles, and dose reduction to 50 mg will be permitted for patients with significant toxicity. If at least 2 patients respond in the initial stage, and additional 15 patients will be enrolled in the second stage.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Overall International Working Group (IWG) 2006 Response Rate [Up to 2 years, 4 months]
Response recorded from the start of the treatment until disease progression/recurrence. All responses must last for at least 8 weeks. Complete Remission (CR): Bone marrow: ≤ 5% myeloblasts with normal maturation of all cell lines, Persistent dysplasia will be noted, Peripheral blood: Hemoglobin ≥ 11 g/dL, Platelets ≥ 100 x 10^9/L, Neutrophils ≥ 1.0 x 10^9/L, Blasts 0% ; Partial Remission (PR): All CR criteria if abnormal before treatment, except: Bone marrow blasts decreased by ≥ 50% over pretreatment but still > 5%, Cellularity and morphology not relevant; Marrow CR or Hematological Improvement (HI): Bone marrow: ≤ 5% myeloblasts and decrease by ≥ 50% over pretreatment Peripheral blood: if HI responses, they will be noted in addition to marrow CR. Further investigation of PF-04449913 would not be warranted if it produced an overall response rate (CR + PR + marrow CR+HI) of 10% or less (p0), and would be warranted if it produced an overall response rate of 30% or more (p1).
Secondary Outcome Measures
- Median Overall Survival (OS) [Up to 2 years, 4 months]
To estimate the overall survival of patients with refractory/relapsed myelodysplastic Syndrome (MDS) and chronic myelo-monocytic leukemia (CMML) treated with PF-0444913. Overall survival will be defined as the time period between the date of the first dose of drug until the time of death.
- Median Event Free Survival [Up to 2 years, 4 months]
To estimate the event-free survival of patients of this population. Event-free survival will be defined as the date of the first dose of study drug until failure (disease progression) or death from any cause.
- Median Time to Transformation to Acute Myeloid Leukemia (AML) [Up to 2 years, 4 months]
To estimate the time to transformation to AML in patients with <20% blasts. In patients with less than 20% blasts, the time to transformation to AML will be defined as the date of the first dose of drug until either the percentage of bone marrow blasts or the percentage of peripheral blasts exceeds 20%, whichever is first.
- Number of Participants With Treatment Emergent Adverse Events [2 years, 4 months]
Treatment emergent adverse events occurring in equal to or more than 10% of participants.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Must have a pathologically confirmed diagnosis by World Health Organization (WHO) Criteria of MDS, CMML, or acute myeloid leukemia (AML) (except acute promyelocytic leukemia) with < 30% bone marrow blasts (RAEB-t by French American British criteria)
-
Hypomethylating agent (azacitidine and/or decitabine) failure, defined as lack of response, disease progression, loss of response, or intolerance as deemed by the study investigator
-
Adequate renal function, as evidenced by a serum creatinine ≤ 2 times the institutional upper limit of normal
-
Adequate hepatic function, as evidenced by a serum bilirubin < 2 times the institutional upper limit of normal and an aspartic transaminase (AST) and alanine transaminase (ALT) < 2 times the institutional upper limit of normal. Indirect hyperbilirubinemia due to Gilbert's disease or hemolysis is permitted.
-
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
-
Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
-
Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria:
-
Patients with a history of prior therapy with another investigational agent within 4 weeks of the first planned dose of PF-0444913
-
Patients may not be receiving any other investigational agents.
-
History of allergic reactions attributed to compounds of similar chemical or biologic composition to PF-04449913
-
Prior therapy with another hedgehog inhibitor
-
Concurrent use of any other agent for MDS, CMML, or AML. Growth factor use with epoetin, darbepoetin, or granulocyte colony-stimulating factor must be terminated at least 2 weeks before initiation of study treatment.
-
Any uncontrolled concurrent illness that would, in the opinion of the investigator, limit compliance with study requirements
-
Second malignancy requiring active therapy
-
A prolonged corrected QT interval (QTc) of ≥480 ms interval on electrocardiogram
-
History of metastatic cancer diagnosed less than 2 years prior to the first planned dose of PF-0444913
-
Uncontrolled concurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
-
Pregnant women are excluded from this study because PF-04449913 is smoothened inhibitor with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with PF-04449913. Breastfeeding should be discontinued if the mother is treated with PF-04449913.
-
Patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy. Therefore, HIV-positive patients receiving combination antiretroviral therapy are excluded from the study because of possible pharmacokinetic interactions with PF-04449913.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | H. Lee Moffitt Cancer Center and Research Institute | Tampa | Florida | United States | 33612 |
Sponsors and Collaborators
- H. Lee Moffitt Cancer Center and Research Institute
- Pfizer
Investigators
- Principal Investigator: Jeffrey Lancet, M.D., H. Lee Moffitt Cancer Center and Research Institute
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- MCC-17302
Study Results
Participant Flow
Recruitment Details | Recruitment began in August 2013 and participants were enrolled at Moffitt Cancer Center between September 2013 and September 2015. |
---|---|
Pre-assignment Detail |
Arm/Group Title | Experimental: PF-04449913 Treatment |
---|---|
Arm/Group Description | Treatment to be administered on an outpatient basis. All participants to be treated with an oral dose PF-04449913 at 100 mg daily in 4-week cycles for a total of 4 cycles. |
Period Title: Overall Study | |
STARTED | 35 |
COMPLETED | 35 |
NOT COMPLETED | 0 |
Baseline Characteristics
Arm/Group Title | Experimental: PF-04449913 Treatment |
---|---|
Arm/Group Description | Treatment to be administered on an outpatient basis. All participants to be treated with an oral dose PF-04449913 at 100 mg daily in 4-week cycles for a total of 4 cycles. |
Overall Participants | 35 |
Age (Count of Participants) | |
<=18 years |
0
0%
|
Between 18 and 65 years |
6
17.1%
|
>=65 years |
29
82.9%
|
Age (years) [Median (Full Range) ] | |
Median (Full Range) [years] |
75
|
Sex: Female, Male (Count of Participants) | |
Female |
11
31.4%
|
Male |
24
68.6%
|
Region of Enrollment (participants) [Number] | |
United States |
35
100%
|
Outcome Measures
Title | Overall International Working Group (IWG) 2006 Response Rate |
---|---|
Description | Response recorded from the start of the treatment until disease progression/recurrence. All responses must last for at least 8 weeks. Complete Remission (CR): Bone marrow: ≤ 5% myeloblasts with normal maturation of all cell lines, Persistent dysplasia will be noted, Peripheral blood: Hemoglobin ≥ 11 g/dL, Platelets ≥ 100 x 10^9/L, Neutrophils ≥ 1.0 x 10^9/L, Blasts 0% ; Partial Remission (PR): All CR criteria if abnormal before treatment, except: Bone marrow blasts decreased by ≥ 50% over pretreatment but still > 5%, Cellularity and morphology not relevant; Marrow CR or Hematological Improvement (HI): Bone marrow: ≤ 5% myeloblasts and decrease by ≥ 50% over pretreatment Peripheral blood: if HI responses, they will be noted in addition to marrow CR. Further investigation of PF-04449913 would not be warranted if it produced an overall response rate (CR + PR + marrow CR+HI) of 10% or less (p0), and would be warranted if it produced an overall response rate of 30% or more (p1). |
Time Frame | Up to 2 years, 4 months |
Outcome Measure Data
Analysis Population Description |
---|
All participants |
Arm/Group Title | Experimental: PF-04449913 Treatment |
---|---|
Arm/Group Description | Treatment to be administered on an outpatient basis. All participants to be treated with an oral dose PF-04449913 at 100 mg daily in 4-week cycles for a total of 4 cycles. |
Measure Participants | 35 |
Complete Remission (CR) |
0
0%
|
Hematological Improvement (HI) |
2
5.7%
|
Stable Disease (SD) |
19
54.3%
|
Progressive Disease (PD) |
14
40%
|
Title | Median Overall Survival (OS) |
---|---|
Description | To estimate the overall survival of patients with refractory/relapsed myelodysplastic Syndrome (MDS) and chronic myelo-monocytic leukemia (CMML) treated with PF-0444913. Overall survival will be defined as the time period between the date of the first dose of drug until the time of death. |
Time Frame | Up to 2 years, 4 months |
Outcome Measure Data
Analysis Population Description |
---|
All participants |
Arm/Group Title | Experimental: PF-04449913 Treatment |
---|---|
Arm/Group Description | Treatment to be administered on an outpatient basis. All participants to be treated with an oral dose PF-04449913 at 100 mg daily in 4-week cycles for a total of 4 cycles. |
Measure Participants | 35 |
Median (95% Confidence Interval) [months] |
10.2
|
Title | Median Event Free Survival |
---|---|
Description | To estimate the event-free survival of patients of this population. Event-free survival will be defined as the date of the first dose of study drug until failure (disease progression) or death from any cause. |
Time Frame | Up to 2 years, 4 months |
Outcome Measure Data
Analysis Population Description |
---|
All participants |
Arm/Group Title | Experimental: PF-04449913 Treatment |
---|---|
Arm/Group Description | Treatment to be administered on an outpatient basis. All participants to be treated with an oral dose PF-04449913 at 100 mg daily in 4-week cycles for a total of 4 cycles. |
Measure Participants | 35 |
Median (95% Confidence Interval) [months] |
6.4
|
Title | Median Time to Transformation to Acute Myeloid Leukemia (AML) |
---|---|
Description | To estimate the time to transformation to AML in patients with <20% blasts. In patients with less than 20% blasts, the time to transformation to AML will be defined as the date of the first dose of drug until either the percentage of bone marrow blasts or the percentage of peripheral blasts exceeds 20%, whichever is first. |
Time Frame | Up to 2 years, 4 months |
Outcome Measure Data
Analysis Population Description |
---|
NA- The median time to AML was not reached due to insufficient number of participants with events. |
Arm/Group Title | Experimental: PF-04449913 Treatment |
---|---|
Arm/Group Description | Treatment to be administered on an outpatient basis. All participants to be treated with an oral dose PF-04449913 at 100 mg daily in 4-week cycles for a total of 4 cycles. |
Measure Participants | 0 |
Title | Number of Participants With Treatment Emergent Adverse Events |
---|---|
Description | Treatment emergent adverse events occurring in equal to or more than 10% of participants. |
Time Frame | 2 years, 4 months |
Outcome Measure Data
Analysis Population Description |
---|
All participants |
Arm/Group Title | Experimental: PF-04449913 Treatment |
---|---|
Arm/Group Description | Treatment to be administered on an outpatient basis. All participants to be treated with an oral dose PF-04449913 at 100 mg daily in 4-week cycles for a total of 4 cycles. |
Measure Participants | 35 |
Grade 1-2 : Pain |
22
62.9%
|
Grade 1-2 : Dysgeusia |
21
60%
|
Grade 1-2 : Nausea |
11
31.4%
|
Grade 1-2 : Anorexia |
11
31.4%
|
Grade 1-2 : Skin/rash |
8
22.9%
|
Grade 1-2 : Oral mucositis |
9
25.7%
|
Grade 1-2 : AST elevated |
8
22.9%
|
Grade 1-2 : Alopecia |
8
22.9%
|
Grade 1-2 : ALT elevated |
6
17.1%
|
Grade 1-2 : Dizziness |
6
17.1%
|
Grade 1-2 : Dyspnea |
5
14.3%
|
Grade 1-2 : Infections |
2
5.7%
|
Grade 1-2 : Fatigue |
6
17.1%
|
Grade 1-2 : Diarrhea |
6
17.1%
|
Grade 1-2 : Constipation |
5
14.3%
|
Grade 1-2 : Fever |
5
14.3%
|
Grade 1-2 : Hyperkalemia |
5
14.3%
|
Grade 1-2 : Hyperglycemia |
4
11.4%
|
Grade 1-2 : Thrombocytopenia |
2
5.7%
|
Grade 1-2 : Headache |
4
11.4%
|
Grade 1-2 : Vomiting |
4
11.4%
|
Grade 3-4 : Pain |
1
2.9%
|
Grade 3-4 : Dysgeusia |
0
0%
|
Grade 3-4 : Nausea |
0
0%
|
Grade 3-4 : Anorexia |
0
0%
|
Grade 3-4 : Skin/rash |
1
2.9%
|
Grade 3-4 : Oral mucositis |
0
0%
|
Grade 3-4 : AST elevated |
0
0%
|
Grade 3-4 : Alopecia |
0
0%
|
Grade 3-4 : ALT elevated |
0
0%
|
Grade 3-4 : Dizziness |
0
0%
|
Grade 3-4 : Dyspnea |
1
2.9%
|
Grade 3-4 : Infections |
4
11.4%
|
Grade 3-4 : Fatigue |
0
0%
|
Grade 3-4 : Diarrhea |
0
0%
|
Grade 3-4 : Constipation |
0
0%
|
Grade 3-4 : Fever |
0
0%
|
Grade 3-4 : Hyperkalemia |
0
0%
|
Grade 3-4 : Hyperglycemia |
0
0%
|
Grade 3-4 : Thrombocytopenia |
2
5.7%
|
Grade 3-4 : Headache |
0
0%
|
Grade 3-4 : Vomiting |
0
0%
|
Adverse Events
Time Frame | 2 years, 4 months | |
---|---|---|
Adverse Event Reporting Description | ||
Arm/Group Title | Experimental: PF-04449913 Treatment | |
Arm/Group Description | Treatment to be administered on an outpatient basis. All participants to be treated with an oral dose PF-04449913 at 100 mg daily in 4-week cycles for a total of 4 cycles. | |
All Cause Mortality |
||
Experimental: PF-04449913 Treatment | ||
Affected / at Risk (%) | # Events | |
Total | / (NaN) | |
Serious Adverse Events |
||
Experimental: PF-04449913 Treatment | ||
Affected / at Risk (%) | # Events | |
Total | 11/35 (31.4%) | |
Blood and lymphatic system disorders | ||
Febrile neutropenia | 1/35 (2.9%) | 2 |
Cardiac disorders | ||
Cardiac arrest | 1/35 (2.9%) | 1 |
Gastrointestinal disorders | ||
Ileus | 1/35 (2.9%) | 2 |
General disorders | ||
Death NOS | 2/35 (5.7%) | 2 |
Infections and infestations | ||
Abdominal infection | 1/35 (2.9%) | 1 |
Bone infection | 1/35 (2.9%) | 1 |
Infections and infestations - Other, GI | 1/35 (2.9%) | 1 |
Infections and infestations - Other, Rhinovirus/Enterovirus | 1/35 (2.9%) | 1 |
Lung infection | 2/35 (5.7%) | 2 |
Sepsis | 1/35 (2.9%) | 1 |
Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, possible DLBCL NHL | 1/35 (2.9%) | 1 |
Nervous system disorders | ||
Intracranial hemorrhage | 2/35 (5.7%) | 2 |
Respiratory, thoracic and mediastinal disorders | ||
Pneumonitis | 1/35 (2.9%) | 1 |
Other (Not Including Serious) Adverse Events |
||
Experimental: PF-04449913 Treatment | ||
Affected / at Risk (%) | # Events | |
Total | 35/35 (100%) | |
Blood and lymphatic system disorders | ||
Anemia | 3/35 (8.6%) | 4 |
Blood and lymphatic system disorders - Other | 2/35 (5.7%) | 2 |
Leukocytosis | 2/35 (5.7%) | 2 |
Cardiac disorders | ||
Chest pain - cardiac | 2/35 (5.7%) | 3 |
Ventricular arrhythmia | 1/35 (2.9%) | 1 |
Eye disorders | ||
Eye disorders - Other, specify | 1/35 (2.9%) | 1 |
Gastrointestinal disorders | ||
Nausea | 11/35 (31.4%) | 13 |
Mucositis oral | 9/35 (25.7%) | 9 |
Diarrhea | 6/35 (17.1%) | 6 |
Constipation | 5/35 (14.3%) | 5 |
Vomiting | 4/35 (11.4%) | 4 |
Abdominal pain | 2/35 (5.7%) | 2 |
Gastrointestinal disorders - Other | 2/35 (5.7%) | 3 |
Rectal hemorrhage | 2/35 (5.7%) | 2 |
Dysphagia | 1/35 (2.9%) | 1 |
Gastroesophageal reflux disease | 1/35 (2.9%) | 1 |
Hemorrhoids | 1/35 (2.9%) | 1 |
Periodontal disease | 1/35 (2.9%) | 1 |
General disorders | ||
Pain | 23/35 (65.7%) | 30 |
Fatigue | 6/35 (17.1%) | 6 |
Fever | 5/35 (14.3%) | 5 |
Edema limbs | 3/35 (8.6%) | 3 |
Flu like symptoms | 2/35 (5.7%) | 2 |
Chills | 1/35 (2.9%) | 1 |
Gait disturbance | 1/35 (2.9%) | 1 |
General disorders and administration site conditions - Other | 1/35 (2.9%) | 1 |
Infusion related reaction | 1/35 (2.9%) | 1 |
Non-cardiac chest pain | 1/35 (2.9%) | 1 |
Hepatobiliary disorders | ||
Hepatobiliary disorders - Other | 1/35 (2.9%) | 1 |
Immune system disorders | ||
Allergic reaction | 1/35 (2.9%) | 1 |
Infections and infestations | ||
Infections and infestations - Other | 4/35 (11.4%) | 7 |
Skin infection | 2/35 (5.7%) | 2 |
Tooth infection | 2/35 (5.7%) | 2 |
Sinusitis | 1/35 (2.9%) | 1 |
Upper respiratory infection | 1/35 (2.9%) | 1 |
Urinary tract infection | 1/35 (2.9%) | 1 |
Injury, poisoning and procedural complications | ||
Fall | 2/35 (5.7%) | 2 |
Injury, poisoning and procedural complications - Other | 1/35 (2.9%) | 1 |
Investigations | ||
Aspartate aminotransferase increased | 8/35 (22.9%) | 9 |
Alanine aminotransferase increased | 6/35 (17.1%) | 10 |
Weight loss | 5/35 (14.3%) | 5 |
Platelet count decreased | 4/35 (11.4%) | 6 |
Alkaline phosphatase increased | 2/35 (5.7%) | 2 |
Creatinine increased | 2/35 (5.7%) | 2 |
Neutrophil count decreased | 2/35 (5.7%) | 2 |
Investigations - Other | 1/35 (2.9%) | 1 |
Metabolism and nutrition disorders | ||
Anorexia | 11/35 (31.4%) | 14 |
Hyperkalemia | 5/35 (14.3%) | 6 |
Hyperglycemia | 4/35 (11.4%) | 4 |
Hypomagnesemia | 2/35 (5.7%) | 3 |
Hyponatremia | 2/35 (5.7%) | 3 |
Dehydration | 1/35 (2.9%) | 2 |
Hypercalcemia | 1/35 (2.9%) | 2 |
Hyperuricemia | 1/35 (2.9%) | 1 |
Hypoalbuminemia | 1/35 (2.9%) | 1 |
Hypocalcemia | 1/35 (2.9%) | 1 |
Hypokalemia | 1/35 (2.9%) | 4 |
Metabolism and nutrition disorders - Other | 1/35 (2.9%) | 2 |
Musculoskeletal and connective tissue disorders | ||
Pain in extremity | 3/35 (8.6%) | 3 |
Arthralgia | 1/35 (2.9%) | 1 |
Back pain | 1/35 (2.9%) | 1 |
Bone pain | 1/35 (2.9%) | 1 |
Generalized muscle weakness | 1/35 (2.9%) | 1 |
Muscle weakness upper limb | 1/35 (2.9%) | 1 |
Musculoskeletal and connective tissue disorder - Other | 1/35 (2.9%) | 1 |
Nervous system disorders | ||
Dysgeusia | 21/35 (60%) | 25 |
Dizziness | 6/35 (17.1%) | 6 |
Headache | 4/35 (11.4%) | 5 |
Memory impairment | 2/35 (5.7%) | 2 |
Peripheral sensory neuropathy | 2/35 (5.7%) | 2 |
Tremor | 2/35 (5.7%) | 2 |
Dysarthria | 1/35 (2.9%) | 1 |
Dysphasia | 1/35 (2.9%) | 1 |
Encephalopathy | 1/35 (2.9%) | 1 |
Nervous system disorders - Other | 1/35 (2.9%) | 1 |
Psychiatric disorders | ||
Confusion | 2/35 (5.7%) | 3 |
Depression | 2/35 (5.7%) | 2 |
Anxiety | 1/35 (2.9%) | 1 |
Renal and urinary disorders | ||
Hematuria | 1/35 (2.9%) | 1 |
Reproductive system and breast disorders | ||
Testicular hemorrhage | 1/35 (2.9%) | 1 |
Respiratory, thoracic and mediastinal disorders | ||
Dyspnea | 6/35 (17.1%) | 7 |
Epistaxis | 2/35 (5.7%) | 4 |
Pneumonitis | 1/35 (2.9%) | 1 |
Cough | 1/35 (2.9%) | 1 |
Skin and subcutaneous tissue disorders | ||
Alopecia | 8/35 (22.9%) | 8 |
Skin and subcutaneous tissue disorders - Other | 5/35 (14.3%) | 6 |
Pruritus | 3/35 (8.6%) | 3 |
Rash maculo-papular | 3/35 (8.6%) | 3 |
Rash acneiform | 2/35 (5.7%) | 2 |
Skin induration | 1/35 (2.9%) | 1 |
Vascular disorders | ||
Flushing | 1/35 (2.9%) | 1 |
Hypertension | 1/35 (2.9%) | 1 |
Hypotension | 1/35 (2.9%) | 1 |
Lymphedema | 1/35 (2.9%) | 1 |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title | Dr. Jeffrey Lancet |
---|---|
Organization | H. Lee Moffitt Cancer Center and Research Institute |
Phone | 813-745-1387 |
jeffrey.lancet@moffitt.org |
- MCC-17302