A Phase 1 interventional study of Volasertib and Volasertib in Myelodysplastic Syndromes, sponsored by Boehringer Ingelheim. Terminated at 1 site in Japan. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2018-08-09.
Sponsored by Boehringer Ingelheim · Phase 1, Interventional, and Treatment
The objectives of this trial are to evaluate the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics and preliminary efficacy of volasertib in two dosing schedules of intravenous volasertib as monotherapy or in combination with azacitidine in patients with myelodysplastic syndrome (MDS) after hypomethylating agents (HMA) treatment failure.
2,165 studies on the registry are indexed under Myelodysplastic Syndromes; 322 are open to participants now.
This study's enrollment of 1 is below the median of 39 across 1,771 interventional studies indexed under Myelodysplastic Syndromes.
Browse Myelodysplastic Syndromes studies →Boehringer Ingelheim is the lead sponsor of 2,297 studies on the registry; 56 are open to participants now.
Of its 166 completed or terminated interventional studies of FDA-regulated products, 121 (73%) have results posted.
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Drug: Volasertib
Drug: Volasertib · Drug: Azacitidine
Number of Patients With Dose Limiting Toxicities (DLT) in the First Cycle
DLT was defined as any of the following adverse events (AEs) considered to be related to study drug: 1. Common terminology criteria for adverse events (CTCAE) v4.03 ≥Grade 3 drug related non- haematological toxicity, excluding; ≥Grade 3 untreated nausea, vomiting or diarrhea. Any laboratory abnormality - not considered clinically significant by investigator or resolved spontaneously or could have been recovered with appropriate treatment within 7 days. Grade 3 infection which could be recovered with appropriate treatment within 7 days. Azacitidine injection site reaction or complications related to azacitidine injection. 2. Febrile neutropenia as defined by CTCAE which could not recovered with appropriate treatment within 7 days. 3. Inability to deliver full dose of volasertib according to the assigned dose level within Cycle 1 due to drug-related AEs. 4. Haematological DLTs. 5. Any other drug-related AEs that resulted in the delay of starting new treatment cycle for ≥4 weeks.
Time frame: First treatment cycle, up to 28 days
Maximum Tolerated Dose (MTD) of Volasertib
The MTD was defined as the highest dose with less than 35% risk of the true dose limiting toxicities (DLT) rate being above 0.33 for schedule A, and the highest dose with less than 40% risk of the true DLT rate being above 0.33 for schedule B. The phase I dose-finding was to be guided by a Bayesian 2-parameter logistic regression model (BLRM) with overdose control in each schedule separately.
Time frame: First treatment cycle, up to 28 days
Objective Response Defined as Best Overall Response of Complete Remission, Partial Remission or Haematological Improvement According to the International Working Group 2006 Criteria
Objective response defined as best overall response of complete remission, partial remission or haematological improvement according to the International Working Group 2006 criteria. It is based on Complete remission (CR): Bone marrow: \<=5% myeloblasts with normal maturation of all cell lines, Peripheral blood: Hemoglobin \>=11 Grams Per Decilitre (g/dL), Platelets \>=100 x 109/L, Neutrophils \>=1.0 x 109/L, Blasts 0%. Peripheral blood responses had to last at least 4 weeks to qualify for CR. Partial remission (PR): All CR criteria if abnormal before treatment except: Bone marrow blasts decreased by \>=50% to baseline but still \>5%, Cellularity and morphology not relevant. Peripheral blood responses must last at least 4 weeks to qualify for PR. Haematological improvement (HI): HI was evaluated in patients with abnormal pretreatment values based on Erythroid response, Platelet response, Neutrophil response. Peripheral blood responses had to last at least 8 weeks to qualify for HI.
Time frame: Up to 168 days
Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to the Last Measured Time Point tz of Volasertib (AUC0-tz) (for Monotherapy)
Area under the plasma concentration-time curve over the time interval from zero to the last measured time point tz of volasertib (AUC0-tz) (for monotherapy).
Time frame: Pharmacokinetic (PK) samples were taken at 5 minutes before drug administration and 0:30, 1:00, 2:00, 3:00, 4:00, 24:00, 167:55, 168:30, 169:00, 169:30, 170:00, 171:00, 172:00, 192:00, 336:00, 504:00, 672:00 hours after drug administration
Maximum Measured Plasma Concentration of Volasertib (Cmax) (for Monotherapy)
Maximum measured plasma concentration of volasertib (Cmax) (for monotherapy).
Time frame: PK samples were taken at 5 minutes before drug administration and 0:30, 1:00, 2:00, 3:00, 4:00, 24:00, 167:55, 168:30, 169:00, 169:30, 170:00, 171:00, 172:00, 192:00, 336:00, 504:00, 672:00 hours after drug administration
Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero Extrapolated to Infinity of Volasertib (AUC0-∞) (for Combination)
Area under the plasma concentration-time curve over the time interval from zero extrapolated to infinity of volasertib (AUC0-∞) (for combination).
Time frame: PK samples were to be taken at 5 minutes before drug administration (167:55) and 168:30, 169:00, 169:30, 170:00, 171:00, 172:00, 192:00, 336:00, 504:00, 672:00 hours after first drug administration of Azacitidine
Maximum Measured Plasma Concentration of Volasertib (Cmax) (for Combination)
Maximum measured plasma concentration of volasertib (Cmax) (for combination).
Time frame: PK samples were to be taken at 5 minutes before drug administration (167:55) and 168:30, 169:00, 169:30, 170:00, 171:00, 172:00, 192:00, 336:00, 504:00, 672:00 hours after first drug administration of Azacitidine
| Milestone | Volasertib Monotherapy | Volasertib + Azacitidine Combination |
|---|---|---|
| Started | 1 | 0 |
| Completed | 0 | 0 |
| Not completed | 1 | 0 |
| Withdrew: Progressive disease/relapse | 1 | 0 |
DLT was defined as any of the following adverse events (AEs) considered to be related to study drug: 1. Common terminology criteria for adverse events (CTCAE) v4.03 ≥Grade 3 drug related non- haematological toxicity, excluding; ≥Grade 3 untreated nausea, vomiting or diarrhea. Any laboratory abnormality - not considered clinically significant by investigator or resolved spontaneously or could have been recovered with appropriate treatment within 7 days. Grade 3 infection which could be recovered with appropriate treatment within 7 days. Azacitidine injection site reaction or complications related to azacitidine injection. 2. Febrile neutropenia as defined by CTCAE which could not recovered with appropriate treatment within 7 days. 3. Inability to deliver full dose of volasertib according to the assigned dose level within Cycle 1 due to drug-related AEs. 4. Haematological DLTs. 5. Any other drug-related AEs that resulted in the delay of starting new treatment cycle for ≥4 weeks.
| Participants | Volasertib Monotherapy | Volasertib + Azacitidine Combination |
|---|---|---|
| Number of Patients With Dose Limiting Toxicities (DLT) in the First Cycle | 0 | — |
The MTD was defined as the highest dose with less than 35% risk of the true dose limiting toxicities (DLT) rate being above 0.33 for schedule A, and the highest dose with less than 40% risk of the true DLT rate being above 0.33 for schedule B. The phase I dose-finding was to be guided by a Bayesian 2-parameter logistic regression model (BLRM) with overdose control in each schedule separately.
| Milligram (mg)/ meter square (m2) | Volasertib Monotherapy | Volasertib + Azacitidine Combination |
|---|---|---|
| Maximum Tolerated Dose (MTD) of Volasertib | NA | — |
Objective response defined as best overall response of complete remission, partial remission or haematological improvement according to the International Working Group 2006 criteria. It is based on Complete remission (CR): Bone marrow: \<=5% myeloblasts with normal maturation of all cell lines, Peripheral blood: Hemoglobin \>=11 Grams Per Decilitre (g/dL), Platelets \>=100 x 109/L, Neutrophils \>=1.0 x 109/L, Blasts 0%. Peripheral blood responses had to last at least 4 weeks to qualify for CR. Partial remission (PR): All CR criteria if abnormal before treatment except: Bone marrow blasts decreased by \>=50% to baseline but still \>5%, Cellularity and morphology not relevant. Peripheral blood responses must last at least 4 weeks to qualify for PR. Haematological improvement (HI): HI was evaluated in patients with abnormal pretreatment values based on Erythroid response, Platelet response, Neutrophil response. Peripheral blood responses had to last at least 8 weeks to qualify for HI.
| Participants | Volasertib Monotherapy | Volasertib + Azacitidine Combination |
|---|---|---|
| Yes | 0 | — |
| No | 1 | — |
Area under the plasma concentration-time curve over the time interval from zero to the last measured time point tz of volasertib (AUC0-tz) (for monotherapy).
| Nanogram(ng)*hour(h)/milliliter(mL) | Volasertib Monotherapy |
|---|---|
| Cycle 1 - Day 1 | 2480 |
| Cycle 1 - Day 8 | 5460 |
Maximum measured plasma concentration of volasertib (Cmax) (for monotherapy).
| Nanogram(ng)*/milliliter(mL) | Volasertib Monotherapy |
|---|---|
| Cycle 1 - Day 1 | 467 |
| Cycle 1 - Day 8 | 553 |
Area under the plasma concentration-time curve over the time interval from zero extrapolated to infinity of volasertib (AUC0-∞) (for combination).
No measurements were reported for this outcome.
Maximum measured plasma concentration of volasertib (Cmax) (for combination).
No measurements were reported for this outcome.
Collected over From first drug administration until 30 days after the last dose of study medication, up to 94 days. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Volasertib Monotherapy | — | 1/1 (100%) | 1/1 (100%) |
| Event | Volasertib Monotherapy |
|---|---|
| Lower gastrointestinal haemorrhageGastrointestinal disorders | 1/1 |
| Event | Volasertib Monotherapy |
|---|---|
| CataractEye disorders | 1/1 |
| Dental cariesGastrointestinal disorders | 1/1 |
| Oral lichen planusGastrointestinal disorders | 1/1 |
| Small intestine ulcerGastrointestinal disorders | 1/1 |
| StomatitisGastrointestinal disorders | 1/1 |
| Infusion site extravasationGeneral disorders | 1/1 |
| Herpes simplexInfections and infestations | 1/1 |
| Injection site infectionInfections and infestations | 1/1 |
| PneumoniaInfections and infestations | 1/1 |
| Weight decreasedInvestigations | 1/1 |
All patients who were documented to receive at least one dose of volasertib were defined as the treated set (TS).
| Age, Continuous(Years) | Volasertib Monotherapy | Volasertib + Azacitidine Combination | Total |
|---|---|---|---|
| Mean | 69 | — | 69 |
| Sex: Female, Male(Participants) | Volasertib Monotherapy | Volasertib + Azacitidine Combination | Total |
|---|---|---|---|
| Female | 0 | — | 0 |
| Male | 1 | — | 1 |
Ran from Apr 2016 to primary completion in Jun 2016, 2 months.
Results were first posted in Aug 2018, 2 years 1 month after primary completion.
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Studies of the drug tested here: Azacitidine