Leukemia, Acute Myeloid, Myelodysplastic Syndrome
Conditions
Brief summary
The primary objective of this study is to evaluate the safety, tolerability, and efficacy of temozolomide in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) participants who are not candidates for standard induction therapy and exhibit low MGMT expression.
Interventions
DRUGtemozolomide
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Confirmed diagnosis of acute myeloid leukemia (AML), any subtype except acute promyelocytic leukemia (APL), by the World Health Organization (WHO) criteria, or high risk MDS with blasts between 10 and 20% in the bone marrow. * No prior AML chemotherapy except hydroxyurea. * Leukemic blast count \<30x10\^9/L at the start of therapy. Prior cytoreduction with hydroxyurea (maximum 14 days) is permitted. * Participant is not a candidate for aggressive induction based on at least one of the following: adverse-risk cytogenetics (complete or partial deletion of 5 or 7, complex \[\>3\] cytogenetic abnormalities, inv3, 11q23 abnormalities); secondary AML (antecedent hematologic disorder or therapy-related AML); comorbid medical illnesses precluding standard induction therapy; participant's refusal of standard induction therapy. * Confirmed low MGMT expression (MGMT: beta-actin ≤0.2), as evaluated by Western blot, or weak MGMT expression defined as \> 0.2 and ≤2.5 if promoter is methylated, upon Sponsor approval. * Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. * Use of medically approved contraception in fertile males and females. * Negative urine or serum pregnancy test for women of childbearing potential (72 hours prior to Baseline).
Exclusion criteria
* Serum bilirubin \>2 times the upper limit of normal (ULN), or serum aspartate aminotransferase/ alanine aminotransferase \>5 times ULN. * Serum creatinine \>200 umol/L. * History of other malignancies within 1 year prior to study entry, with the exception of localized nonmelanomatous skin cancer or cervical cancer in situ. * Presence of active uncontrolled infection. * Known human immunodeficiency virus (HIV) infection. * Any medical condition that may interfere with protocol evaluation or oral medication intake. * Prior chemotherapy other than hydroxyurea.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Response at the End of Temozolomide Induction | at the end of each cycle (approximately 4 weeks post start of cycle), up to a maximum 63 weeks | Complete Response (CR): \< 5% blasts in normocellular bone marrow (BM); Absolute Neutrophil Count (ANC) \> 1.0 x 10\^9/L, platelets \> 100 x 10\^9/L, and no extramedullary disease. CR with incomplete platelet recovery (CRp): All the criteria of CR but with platelets \< 100 x 10\^9/L but ≥ 50 x 10\^9/L and platelet transfusion independent. Morphologic leukemia-free state (MLFS): complete clearance of blasts from marrow and blood, but criteria for CR or CRp not met. Partial response (PR): decrease ≥ 50% BM blasts. Minimal Response (MR): decrease ≥ 25% but \<50% BM blasts. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Relapse-free Survival in Participants Achieving CR or CRp and Proceeding to Reduced Dose-intensity Maintenance Therapy With Temozolomide | Start of treatment until disease progression [up to 1 year after treatment ends (up to 115 weeks)] | Relapse-free survival was defined as time to disease progression. Complete Response (CR): \< 5% blasts in normocellular bone marrow (BM); Absolute Neutrophil Count (ANC) \> 1.0 x 10\^9/L, platelets \> 100 x 10\^9/L, and no extramedullary disease. CR with incomplete platelet recovery (CRp): All the criteria of CR but with platelets \< 100 x 10\^9/L but ≥ 50 x 10\^9/L and platelet transfusion independent. |
| Overall Survival (OS) in Participants Achieving CR or CRp and Proceeding to Reduced Dose-intensity Maintenance Therapy With Temozolomide | Start of treatment until death or end of study [up to 1 year after treatment ends (up to 115 weeks)] | OS was defined as the time from start of treatment until death or end of study. Complete Response (CR): \< 5% blasts in normocellular bone marrow (BM); Absolute Neutrophil Count (ANC) \> 1.0 x 10\^9/L, platelets \> 100 x 10\^9/L, and no extramedullary disease. CR with incomplete platelet recovery (CRp): All the criteria of CR but with platelets \< 100 x 10\^9/L but ≥ 50 x 10\^9/L and platelet transfusion independent. |
| Number of Previously Untreated Participants With Low O6-Methylguanine Methyltransferase (MGMT) Expression | Baseline | Low MGMT expression was defined as MGMT/β-actin ratio \< 0.2. MGMT & β-actin are cancer biomarkers. |
| MGMT Expression in Leukemic Blasts at the Time of Relapse | Up to 1 year after treatment ends (up to 115 weeks) | Low MGMT expression was defined as MGMT/β-actin ratio of \<0.2. MGMT & β-actin are cancer biomarkers. |
| Duration of Response in Participants Achieving Complete Response (CR) and Proceeding to Reduced Dose-intensity Maintenance Therapy With Temozolomide | Up to 1 year after treatment ends (up to 115 weeks) | Complete Response (CR): \< 5% blasts in normocellular bone marrow (BM); Absolute Neutrophil Count (ANC) \> 1.0 x 10\^9/L, platelets \> 100 x 10\^9/L, and no extramedullary disease. |
| Progression-free Survival for Participants Achieving PR, MLSF, or MR | Start of treatment until disease progression [up to 1 year after treatment ends (up to 115 weeks)] | Progression-free survival was defined as time to disease progression. Morphologic leukemia-free state (MLFS): complete clearance of blasts from marrow and blood, but criteria for CR or CRp not met. Partial response (PR): decrease ≥ 50% BM blasts. Minimal Response (MR): decrease ≥ 25% but \<50% BM blasts. |
| Quality of Life (QoL) in Participants Receiving Long Term Temozolomide Therapy Assessed by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-30 | Baseline and post-study visit (63 weeks) | The EORTC QLQ-C30 was a 30-item questionnaire developed to assess the QoL of cancer patients. Scores ranged from 0 -100. For functional and global QoL scales, higher scores meant a better level of function. For symptom-oriented scales, a higher score meant more severe symptoms and a decrease in QoL. |
| Quality of Life (QoL) in Participants Receiving Long Term Temozolomide Therapy Assessed by EORTC QLQ-LC13 | Baseline and post-study visit (63 weeks) | The EORTC QLQ-LC13 was a 13-item questionnaire developed to supplement the EORTC QLQ-C30 in lung cancer patients. It had a score range 0-100 with higher scores representing an increase in symptoms. |
| Quality of Life (QoL) in Participants Receiving Long Term Temozolomide Therapy Assessed by Functional Assessment of Cancer Therapy (FACT)-G | Baseline and post-study visit (63 weeks) | The FACT-G was a 27-item questionnaire developed to assess the QoL in patients with chronic illnesses. Scores ranged from 0 to 28. For physical well being, lower scores indicated a better outcome. For functional well being, higher scores indicated a better outcome. For social & emotional well being, whether a high score or a lower one indicated a better outcome depended on the question. |
| Number of Participants With CR, PR, or MLFS Who Received Modified Low Dose Maintenance Therapy (100 mg/m^2/Day x21 Days of Each 28 Day Cycle) and Experienced Toxicity | From first dose to 30 days after last dose of study drug (up to 67 weeks) | Toxicity was defined as any adverse event experienced by a participant regardless of causal relationship with study treatment. An adverse event (AE) was defined as any untoward medical occurrence in a participant administered a pharmaceutical product, biologic (at any dose), or medical device, which did not necessarily have a causal relationship with the treatment. Adverse events may have included the onset of new illness and/or the exacerbation of preexisting conditions. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Temozolomide Temozolomide capsules orally, once daily: 1 induction cycle (200 mg/m\^2/day for 7 days in 1 28 day cycle), 1 consolidation cycle (200 mg/m\^2/day for 7 days in 1 28 day cycle), then 200 mg/m\^2/day for 7 days each 28-day cycle or for 5 days each 28-day cycle (12 cycle maximum). Alternatively participants could have received 100 mg/m\^2/day for 21 days of each 28-day cycle (12 cycle maximum). | 47 |
| Total | 47 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 25 |
| Overall Study | Excluded from efficacy evaluations | 6 |
| Overall Study | Screen failure | 148 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Temozolomide |
|---|---|
| Age, Continuous | 75 years |
| Region of Enrollment Canada | 47 participants |
| Sex: Female, Male Female | 18 Participants |
| Sex: Female, Male Male | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 45 / 47 |
| serious Total, serious adverse events | 25 / 47 |
Outcome results
Primary
Clinical Response at the End of Temozolomide Induction
Complete Response (CR): \< 5% blasts in normocellular bone marrow (BM); Absolute Neutrophil Count (ANC) \> 1.0 x 10\^9/L, platelets \> 100 x 10\^9/L, and no extramedullary disease. CR with incomplete platelet recovery (CRp): All the criteria of CR but with platelets \< 100 x 10\^9/L but ≥ 50 x 10\^9/L and platelet transfusion independent. Morphologic leukemia-free state (MLFS): complete clearance of blasts from marrow and blood, but criteria for CR or CRp not met. Partial response (PR): decrease ≥ 50% BM blasts. Minimal Response (MR): decrease ≥ 25% but \<50% BM blasts.
Time frame: at the end of each cycle (approximately 4 weeks post start of cycle), up to a maximum 63 weeks
Population: Efficacy evaluable population (all eligible participants who completed at least one additional disease evaluation after baseline)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Temozolomide | Clinical Response at the End of Temozolomide Induction | PR | 8 participants |
| Temozolomide | Clinical Response at the End of Temozolomide Induction | MR | 7 participants |
| Temozolomide | Clinical Response at the End of Temozolomide Induction | CR | 10 participants |
| Temozolomide | Clinical Response at the End of Temozolomide Induction | CRp | 2 participants |
| Temozolomide | Clinical Response at the End of Temozolomide Induction | MLFS | 4 participants |
Secondary
Duration of Response in Participants Achieving Complete Response (CR) and Proceeding to Reduced Dose-intensity Maintenance Therapy With Temozolomide
Complete Response (CR): \< 5% blasts in normocellular bone marrow (BM); Absolute Neutrophil Count (ANC) \> 1.0 x 10\^9/L, platelets \> 100 x 10\^9/L, and no extramedullary disease.
Time frame: Up to 1 year after treatment ends (up to 115 weeks)
Population: Efficacy evaluable population (all eligible participants who completed at least one additional disease evaluation after baseline)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Temozolomide | Duration of Response in Participants Achieving Complete Response (CR) and Proceeding to Reduced Dose-intensity Maintenance Therapy With Temozolomide | 408 Days |
Secondary
MGMT Expression in Leukemic Blasts at the Time of Relapse
Low MGMT expression was defined as MGMT/β-actin ratio of \<0.2. MGMT & β-actin are cancer biomarkers.
Time frame: Up to 1 year after treatment ends (up to 115 weeks)
Population: Analysis could not be performed due to lack of specimens.
Secondary
Number of Participants With CR, PR, or MLFS Who Received Modified Low Dose Maintenance Therapy (100 mg/m^2/Day x21 Days of Each 28 Day Cycle) and Experienced Toxicity
Toxicity was defined as any adverse event experienced by a participant regardless of causal relationship with study treatment. An adverse event (AE) was defined as any untoward medical occurrence in a participant administered a pharmaceutical product, biologic (at any dose), or medical device, which did not necessarily have a causal relationship with the treatment. Adverse events may have included the onset of new illness and/or the exacerbation of preexisting conditions.
Time frame: From first dose to 30 days after last dose of study drug (up to 67 weeks)
Population: Number of participants who achieved CR, PR, or MLFS and received modified low dose maintenance therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Temozolomide | Number of Participants With CR, PR, or MLFS Who Received Modified Low Dose Maintenance Therapy (100 mg/m^2/Day x21 Days of Each 28 Day Cycle) and Experienced Toxicity | 1 participants |
Secondary
Number of Previously Untreated Participants With Low O6-Methylguanine Methyltransferase (MGMT) Expression
Low MGMT expression was defined as MGMT/β-actin ratio \< 0.2. MGMT & β-actin are cancer biomarkers.
Time frame: Baseline
Population: All screened participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Temozolomide | Number of Previously Untreated Participants With Low O6-Methylguanine Methyltransferase (MGMT) Expression | 81 participants |
Secondary
Overall Survival (OS) in Participants Achieving CR or CRp and Proceeding to Reduced Dose-intensity Maintenance Therapy With Temozolomide
OS was defined as the time from start of treatment until death or end of study. Complete Response (CR): \< 5% blasts in normocellular bone marrow (BM); Absolute Neutrophil Count (ANC) \> 1.0 x 10\^9/L, platelets \> 100 x 10\^9/L, and no extramedullary disease. CR with incomplete platelet recovery (CRp): All the criteria of CR but with platelets \< 100 x 10\^9/L but ≥ 50 x 10\^9/L and platelet transfusion independent.
Time frame: Start of treatment until death or end of study [up to 1 year after treatment ends (up to 115 weeks)]
Population: Efficacy evaluable population (all eligible participants who completed at least one additional disease evaluation after baseline)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Temozolomide | Overall Survival (OS) in Participants Achieving CR or CRp and Proceeding to Reduced Dose-intensity Maintenance Therapy With Temozolomide | 21.4 months |
Secondary
Progression-free Survival for Participants Achieving PR, MLSF, or MR
Progression-free survival was defined as time to disease progression. Morphologic leukemia-free state (MLFS): complete clearance of blasts from marrow and blood, but criteria for CR or CRp not met. Partial response (PR): decrease ≥ 50% BM blasts. Minimal Response (MR): decrease ≥ 25% but \<50% BM blasts.
Time frame: Start of treatment until disease progression [up to 1 year after treatment ends (up to 115 weeks)]
Population: Efficacy evaluable population (all eligible participants who completed at least one additional disease evaluation after baseline) who achieved PR, MLSF, or MR
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Temozolomide | Progression-free Survival for Participants Achieving PR, MLSF, or MR | 1.6 months |
Secondary
Quality of Life (QoL) in Participants Receiving Long Term Temozolomide Therapy Assessed by EORTC QLQ-LC13
The EORTC QLQ-LC13 was a 13-item questionnaire developed to supplement the EORTC QLQ-C30 in lung cancer patients. It had a score range 0-100 with higher scores representing an increase in symptoms.
Time frame: Baseline and post-study visit (63 weeks)
Population: Analysis could not be performed due to incomplete data.
Secondary
Quality of Life (QoL) in Participants Receiving Long Term Temozolomide Therapy Assessed by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-30
The EORTC QLQ-C30 was a 30-item questionnaire developed to assess the QoL of cancer patients. Scores ranged from 0 -100. For functional and global QoL scales, higher scores meant a better level of function. For symptom-oriented scales, a higher score meant more severe symptoms and a decrease in QoL.
Time frame: Baseline and post-study visit (63 weeks)
Population: Analysis could not be performed due to incomplete data.
Secondary
Quality of Life (QoL) in Participants Receiving Long Term Temozolomide Therapy Assessed by Functional Assessment of Cancer Therapy (FACT)-G
The FACT-G was a 27-item questionnaire developed to assess the QoL in patients with chronic illnesses. Scores ranged from 0 to 28. For physical well being, lower scores indicated a better outcome. For functional well being, higher scores indicated a better outcome. For social & emotional well being, whether a high score or a lower one indicated a better outcome depended on the question.
Time frame: Baseline and post-study visit (63 weeks)
Population: Analysis could not be performed due to incomplete data.
Secondary
Relapse-free Survival in Participants Achieving CR or CRp and Proceeding to Reduced Dose-intensity Maintenance Therapy With Temozolomide
Relapse-free survival was defined as time to disease progression. Complete Response (CR): \< 5% blasts in normocellular bone marrow (BM); Absolute Neutrophil Count (ANC) \> 1.0 x 10\^9/L, platelets \> 100 x 10\^9/L, and no extramedullary disease. CR with incomplete platelet recovery (CRp): All the criteria of CR but with platelets \< 100 x 10\^9/L but ≥ 50 x 10\^9/L and platelet transfusion independent.
Time frame: Start of treatment until disease progression [up to 1 year after treatment ends (up to 115 weeks)]
Population: Efficacy evaluable population (all eligible participants who completed at least one additional disease evaluation after baseline)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Temozolomide | Relapse-free Survival in Participants Achieving CR or CRp and Proceeding to Reduced Dose-intensity Maintenance Therapy With Temozolomide | 10.5 months |