Invasive Aspergillosis
Conditions
Keywords
aspergillosis, caspofungin, maximum tolerated dose
Brief summary
This study investigates the safety and tolerability as well as the efficacy and pharmacokinetics of caspofungin in four escalating dosages in adult patients with hematologic malignancies and proven or probable invasive aspergillosis.
Detailed description
Due to its efficacy and a broad antifungal spectrum against relevant fungal pathogens, lack of cross-resistance to azoles and amphotericin B, documented efficacy against human Aspergillus infections, favorable pharmacokinetic properties, and excellent tolerability according to the current data, caspofungin is a highly promising candidate for improving the results of treatment of invasive fungal infections. Preclinical and clinical data indicate a dose dependent antifungal efficacy of caspofungin as well as of other echinocandins such as micafungin and anidulafungin. Thus it appears reasonable to investigate the impact of higher doses of caspofungin to improve the results already achieved with this component so far. The maximum tolerated dose (MTD) of caspofungin and the distribution of the drug in patients following administration of doses of 70 mg or more are not yet known. We therefore investigate the safety, tolerability and pharmacokinetics of caspofungin in rising doses in a dose escalation study in adult patients with proven or probable invasive aspergillosis.
Interventions
DRUGcaspofungin
i.v.
Sponsors
University of Cologne
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Immunocompromised due to hematologic malignancies, bone marrow failure syndromes, hematopoietic stem cell transplantation, solid organ transplantation, other conditions resulting in severe neutropenia, HIV infection, prolonged corticosteroid therapy, treatment with other immunosuppressive medications, or other immunocompromising conditions that place patients at risk for invasive fungal infections. * Evidence of proven or probable invasive aspergillosis, by modified EORTC criteria
Exclusion criteria
* Concomitant other systemic antifungal agents are not permitted on study. * Chronic invasive fungal infection, defined as signs/symptoms of invasive fungal infection present for \> 4 weeks preceding entry into study * Prior systemic therapy of ≥ 4 days with any polyene anti-fungal agent within 14 days of study enrollment * Prior systemic therapy of ≥ 4 days with non-polyenes for the current, documented IFI.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability of Caspofungin in Four Escalating Dosages in Adult Patients With Hematologic Malignancies and Proven or Probable Invasive Aspergillosis | End of caspofungin treatment, treatment duration varied between 3 and 29 days (mean: 20.5; median: 24.5) | Endpoints of safety and tolerability are the number of toxicity-related study therapy discontinuations and grade III and IV clinical and laboratory events, as evaluated on the basis of current NCI criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of Caspofungin in Four Escalating Dosages in the Treatment of Proven or Probable Invasive Aspergillosis. | End of caspofungin treatment; 4 weeks follow-up; 12 weeks follow-up | Numbers of patients in each dose cohort according to invasive aspergillosis (IA) outcome at end of protocol treatment (EOT), 4 weeks follow-up (4w FU) and 12 weeks follow-up (12w FU), respectively. 12w FU was only required for patients with a CR or PR at the 4w FU. Definitions: CR: resolution of all attributable symptoms, signs, and radiographic or bronchoscopic abnormalities. PR: clinically meaningful improvement in attributable symptoms, signs, and radiographic (min. 50% decrease) or bronchoscopic abnormalities. Stable disease (SD): no improvement in attributable symptoms, signs, and radiographic or bronchoscopic abnormalities. Failure: deterioration in attributable clinical or radiographic abnormalities necessitating alternative antifungal therapy or resulting in death. Relapse: reemergence of IA after EOT following CR, PR or SD or early withdrawal. |
Countries
Belgium, Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 1st Cohort 70mg 1x/day
caspofungin : i.v. | 9 |
| 2nd Cohort 100mg 1x/day
caspofungin : i.v. | 8 |
| 3rd Cohort 150mg 1x/day
caspofungin : i.v. | 9 |
| 4th Cohort 200mg 1x/day
caspofungin : i.v. | 20 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 0 |
| Overall Study | Death | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | 4th Cohort | 1st Cohort | 3rd Cohort | 2nd Cohort |
|---|---|---|---|---|---|
| Age, Customized <=30 years | 2 participants | 1 participants | 0 participants | 0 participants | 1 participants |
| Age, Customized > 70 years | 8 participants | 5 participants | 1 participants | 1 participants | 1 participants |
| Age, Customized Between 30 and 40 years | 6 participants | 2 participants | 2 participants | 1 participants | 1 participants |
| Age, Customized Between 40 and 50 years | 6 participants | 2 participants | 1 participants | 2 participants | 1 participants |
| Age, Customized Between 50 and 60 years | 7 participants | 3 participants | 3 participants | 1 participants | 0 participants |
| Age, Customized Between 60 and 70 years | 17 participants | 7 participants | 2 participants | 4 participants | 4 participants |
| Region of Enrollment Germany | 46 participants | 20 participants | 9 participants | 9 participants | 8 participants |
| Sex: Female, Male Female | 21 Participants | 10 Participants | 2 Participants | 4 Participants | 5 Participants |
| Sex: Female, Male Male | 25 Participants | 10 Participants | 7 Participants | 5 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 9 / 9 | 8 / 8 | 9 / 9 | 20 / 20 |
| serious Total, serious adverse events | 1 / 9 | 5 / 8 | 7 / 9 | 12 / 20 |
Outcome results
Primary
Safety and Tolerability of Caspofungin in Four Escalating Dosages in Adult Patients With Hematologic Malignancies and Proven or Probable Invasive Aspergillosis
Endpoints of safety and tolerability are the number of toxicity-related study therapy discontinuations and grade III and IV clinical and laboratory events, as evaluated on the basis of current NCI criteria.
Time frame: End of caspofungin treatment, treatment duration varied between 3 and 29 days (mean: 20.5; median: 24.5)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 1st Cohort | Safety and Tolerability of Caspofungin in Four Escalating Dosages in Adult Patients With Hematologic Malignancies and Proven or Probable Invasive Aspergillosis | Treatment-emergent AEs (grade 3 to 5) | 11 events |
| 1st Cohort | Safety and Tolerability of Caspofungin in Four Escalating Dosages in Adult Patients With Hematologic Malignancies and Proven or Probable Invasive Aspergillosis | At least probably related AEs (grade 3 to 5) | 0 events |
| 1st Cohort | Safety and Tolerability of Caspofungin in Four Escalating Dosages in Adult Patients With Hematologic Malignancies and Proven or Probable Invasive Aspergillosis | At least possibly related AEs (grade 3 to 5) | 0 events |
| 2nd Cohort | Safety and Tolerability of Caspofungin in Four Escalating Dosages in Adult Patients With Hematologic Malignancies and Proven or Probable Invasive Aspergillosis | Treatment-emergent AEs (grade 3 to 5) | 12 events |
| 2nd Cohort | Safety and Tolerability of Caspofungin in Four Escalating Dosages in Adult Patients With Hematologic Malignancies and Proven or Probable Invasive Aspergillosis | At least probably related AEs (grade 3 to 5) | 0 events |
| 2nd Cohort | Safety and Tolerability of Caspofungin in Four Escalating Dosages in Adult Patients With Hematologic Malignancies and Proven or Probable Invasive Aspergillosis | At least possibly related AEs (grade 3 to 5) | 0 events |
| 3rd Cohort | Safety and Tolerability of Caspofungin in Four Escalating Dosages in Adult Patients With Hematologic Malignancies and Proven or Probable Invasive Aspergillosis | At least possibly related AEs (grade 3 to 5) | 0 events |
| 3rd Cohort | Safety and Tolerability of Caspofungin in Four Escalating Dosages in Adult Patients With Hematologic Malignancies and Proven or Probable Invasive Aspergillosis | Treatment-emergent AEs (grade 3 to 5) | 9 events |
| 3rd Cohort | Safety and Tolerability of Caspofungin in Four Escalating Dosages in Adult Patients With Hematologic Malignancies and Proven or Probable Invasive Aspergillosis | At least probably related AEs (grade 3 to 5) | 0 events |
| 4th Cohort | Safety and Tolerability of Caspofungin in Four Escalating Dosages in Adult Patients With Hematologic Malignancies and Proven or Probable Invasive Aspergillosis | Treatment-emergent AEs (grade 3 to 5) | 73 events |
| 4th Cohort | Safety and Tolerability of Caspofungin in Four Escalating Dosages in Adult Patients With Hematologic Malignancies and Proven or Probable Invasive Aspergillosis | At least probably related AEs (grade 3 to 5) | 1 events |
| 4th Cohort | Safety and Tolerability of Caspofungin in Four Escalating Dosages in Adult Patients With Hematologic Malignancies and Proven or Probable Invasive Aspergillosis | At least possibly related AEs (grade 3 to 5) | 6 events |
Secondary
Efficacy of Caspofungin in Four Escalating Dosages in the Treatment of Proven or Probable Invasive Aspergillosis.
Numbers of patients in each dose cohort according to invasive aspergillosis (IA) outcome at end of protocol treatment (EOT), 4 weeks follow-up (4w FU) and 12 weeks follow-up (12w FU), respectively. 12w FU was only required for patients with a CR or PR at the 4w FU. Definitions: CR: resolution of all attributable symptoms, signs, and radiographic or bronchoscopic abnormalities. PR: clinically meaningful improvement in attributable symptoms, signs, and radiographic (min. 50% decrease) or bronchoscopic abnormalities. Stable disease (SD): no improvement in attributable symptoms, signs, and radiographic or bronchoscopic abnormalities. Failure: deterioration in attributable clinical or radiographic abnormalities necessitating alternative antifungal therapy or resulting in death. Relapse: reemergence of IA after EOT following CR, PR or SD or early withdrawal.
Time frame: End of caspofungin treatment; 4 weeks follow-up; 12 weeks follow-up
Population: All 46 recruited patients were included in the analysis. 2 (EOT), 16 (4w FU) and 23 (12w FU) outcomes out of 46 were not recorded.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 1st Cohort | Efficacy of Caspofungin in Four Escalating Dosages in the Treatment of Proven or Probable Invasive Aspergillosis. | Favorable Response (CR&PR) | 4 participants |
| 1st Cohort | Efficacy of Caspofungin in Four Escalating Dosages in the Treatment of Proven or Probable Invasive Aspergillosis. | Relapse (from Favorable Response) 4w post EOT | 0 participants |
| 1st Cohort | Efficacy of Caspofungin in Four Escalating Dosages in the Treatment of Proven or Probable Invasive Aspergillosis. | Failure | 3 participants |
| 1st Cohort | Efficacy of Caspofungin in Four Escalating Dosages in the Treatment of Proven or Probable Invasive Aspergillosis. | Complete Response (CR) | 0 participants |
| 1st Cohort | Efficacy of Caspofungin in Four Escalating Dosages in the Treatment of Proven or Probable Invasive Aspergillosis. | Relapse (from Favorable Response) 12w post EOT | 1 participants |
| 1st Cohort | Efficacy of Caspofungin in Four Escalating Dosages in the Treatment of Proven or Probable Invasive Aspergillosis. | Partial Response (PR) | 4 participants |
| 1st Cohort | Efficacy of Caspofungin in Four Escalating Dosages in the Treatment of Proven or Probable Invasive Aspergillosis. | Stable Disease | 2 participants |
| 2nd Cohort | Efficacy of Caspofungin in Four Escalating Dosages in the Treatment of Proven or Probable Invasive Aspergillosis. | Relapse (from Favorable Response) 4w post EOT | 0 participants |
| 2nd Cohort | Efficacy of Caspofungin in Four Escalating Dosages in the Treatment of Proven or Probable Invasive Aspergillosis. | Stable Disease | 0 participants |
| 2nd Cohort | Efficacy of Caspofungin in Four Escalating Dosages in the Treatment of Proven or Probable Invasive Aspergillosis. | Partial Response (PR) | 3 participants |
| 2nd Cohort | Efficacy of Caspofungin in Four Escalating Dosages in the Treatment of Proven or Probable Invasive Aspergillosis. | Failure | 4 participants |
| 2nd Cohort | Efficacy of Caspofungin in Four Escalating Dosages in the Treatment of Proven or Probable Invasive Aspergillosis. | Relapse (from Favorable Response) 12w post EOT | 0 participants |
| 2nd Cohort | Efficacy of Caspofungin in Four Escalating Dosages in the Treatment of Proven or Probable Invasive Aspergillosis. | Complete Response (CR) | 0 participants |
| 2nd Cohort | Efficacy of Caspofungin in Four Escalating Dosages in the Treatment of Proven or Probable Invasive Aspergillosis. | Favorable Response (CR&PR) | 3 participants |
| 3rd Cohort | Efficacy of Caspofungin in Four Escalating Dosages in the Treatment of Proven or Probable Invasive Aspergillosis. | Stable Disease | 2 participants |
| 3rd Cohort | Efficacy of Caspofungin in Four Escalating Dosages in the Treatment of Proven or Probable Invasive Aspergillosis. | Favorable Response (CR&PR) | 6 participants |
| 3rd Cohort | Efficacy of Caspofungin in Four Escalating Dosages in the Treatment of Proven or Probable Invasive Aspergillosis. | Complete Response (CR) | 1 participants |
| 3rd Cohort | Efficacy of Caspofungin in Four Escalating Dosages in the Treatment of Proven or Probable Invasive Aspergillosis. | Partial Response (PR) | 5 participants |
| 3rd Cohort | Efficacy of Caspofungin in Four Escalating Dosages in the Treatment of Proven or Probable Invasive Aspergillosis. | Failure | 0 participants |
| 3rd Cohort | Efficacy of Caspofungin in Four Escalating Dosages in the Treatment of Proven or Probable Invasive Aspergillosis. | Relapse (from Favorable Response) 4w post EOT | 2 participants |
| 3rd Cohort | Efficacy of Caspofungin in Four Escalating Dosages in the Treatment of Proven or Probable Invasive Aspergillosis. | Relapse (from Favorable Response) 12w post EOT | 2 participants |
| 4th Cohort | Efficacy of Caspofungin in Four Escalating Dosages in the Treatment of Proven or Probable Invasive Aspergillosis. | Partial Response (PR) | 12 participants |
| 4th Cohort | Efficacy of Caspofungin in Four Escalating Dosages in the Treatment of Proven or Probable Invasive Aspergillosis. | Relapse (from Favorable Response) 12w post EOT | 3 participants |
| 4th Cohort | Efficacy of Caspofungin in Four Escalating Dosages in the Treatment of Proven or Probable Invasive Aspergillosis. | Relapse (from Favorable Response) 4w post EOT | 3 participants |
| 4th Cohort | Efficacy of Caspofungin in Four Escalating Dosages in the Treatment of Proven or Probable Invasive Aspergillosis. | Complete Response (CR) | 0 participants |
| 4th Cohort | Efficacy of Caspofungin in Four Escalating Dosages in the Treatment of Proven or Probable Invasive Aspergillosis. | Favorable Response (CR&PR) | 12 participants |
| 4th Cohort | Efficacy of Caspofungin in Four Escalating Dosages in the Treatment of Proven or Probable Invasive Aspergillosis. | Failure | 8 participants |
| 4th Cohort | Efficacy of Caspofungin in Four Escalating Dosages in the Treatment of Proven or Probable Invasive Aspergillosis. | Stable Disease | 0 participants |