Advanced Solid Tumors
Conditions
Brief summary
Prospective, open-label, two-way crossover, phase Ib drug-drug interaction study in patients with advanced solid tumors
Detailed description
Prospective, open-label, two-way crossover, phase Ib drug-drug interaction study in patients with advanced solid tumors. The study will include a pre-treatment (screening) phase (within 14 days before the first lurbinectedin or itraconazole administration) followed by a treatment phase consisting of two lurbinectedin cycles, one cycle in combination with itraconazole and one cycle as single agent (in different order depending on the study sequence), and one additional third cycle of lurbinectedin as a single agent for patients who meet the continuation criteria and obtain a clinical benefit after the first two cycles, and then follow-up of adverse events if any.
Interventions
DRUGLurbinectedin alone
The dose of lurbinectedin during Parts A and B will be 3.2 mg/m² for all patients when administered without itraconazole.
DRUGLurbinectedin+Itraconazole co-administration
The dose of lurbinectedin when given in combination with itraconazole for the initial three patients in Part A will be 0.8 mg/m², and in Part B is susceptible to be adjusted properly if deemed necessary based on exposure and safety experience in Part A.
Sponsors
PharmaMar
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a prospective, open-label, two-way crossover, phase Ib drug-drug interaction study in patients with advanced solid tumors.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Voluntary signed and dated written informed consent prior to any specific study procedure. 2. Male or female with age ≥ 18 years. 3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤ 1 (App. 1). 4. Life expectancy \> 3 months. 5. Pathologically confirmed diagnosis of advanced solid tumors \[except for primary central nervous system (CNS) tumors\], for which no standard therapy exists. 6. Recovery to grade ≤ 1 from drug-related adverse events (AEs) of previous treatments, excluding alopecia and grade 1/2 asthenia or fatigue, according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE v.5). 7. Laboratory values within fourteen days prior to Day 1 of Cycle 1 8. Left ventricular ejection fraction (LVEF) by echocardiography (ECHO) or multiple-gated acquisition (MUGA) within normal range (according to institutional standards). 9. Evidence of non-childbearing status for women of childbearing potential (WOCBP). WOCBP must agree to use a highly effective contraceptive measure up to six months after treatment discontinuation. Valid methods to determine the childbearing potential, adequate contraception and requirements for WOCBP partners are described in App. 2. Fertile male patients with WOCBP partners should use condoms during treatment and for four months following the last investigational medicinal product (IMP) dose.
Exclusion criteria
1. Concomitant diseases/conditions: 1. History or presence of unstable angina, myocardial infarction, congestive heart failure, or clinically significant valvular disease within last year. 2. Symptomatic arrhythmia or any uncontrolled arrhythmia requiring ongoing treatment. 3. Known cirrhosis, alcohol induced steatosis, or chronic active hepatitis. For hepatitis B, this includes positive test for both Hepatitis B surface antigen (HBsAg) and quantitative Hepatitis B polymerase chain reaction (PCR or HVB-DNA+). For hepatitis C, this includes positive test for both Hepatitis C antibody and quantitative Hepatitis C by PCR (or HVC-RNA+). 4. History of obstructive cholestatic liver disease (suitable for stenting procedure) or biliary sepsis in the past 2 months. 5. Known of active COVID-19 disease (this includes positive test for SARS-CoV- 2 in nasopharyngeal/oropharyngeal swabs or nasal swabs by PCR). 2. Symptomatic, progressive or corticosteroids-requiring documented brain metastases or leptomeningeal disease involvement. Patients with asymptomatic documented stable brain metastases not requiring corticosteroids during the last four weeks are allowed. 3. Use of (strong or moderate) inhibitors or inducers of CYP3A4 activity within three weeks prior to Day 1 of Cycle 1. 4. Use of CYP3A4 substrates such as HMG-CoA reductase inhibitors such as atorvastatin, lovastatin and simvastatin for which concomitant administration with strong CYP3A4 inhibitor is contraindicated (App 3). 5. Treatment with any investigational product within the 30 days before Day 1 of Cycle 1. 6. Women who are pregnant or breast feeding and fertile patients (men and women) who are not using an effective method of contraception (see App 2). 7. Psychiatric illness/social situations that would limit compliance with study requirements.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic Analysis: Dose-adjusted AUC(0-∞) | Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days) | The primary parameter of interest for the statistical analysis will be plasma dose adjusted AUC(0-∞) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic Analysis: Dose-normalized AUC(0-t) | Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days) | The dose-normalized area under the concentration-time curve (AUC) will be calculated using the linear-log trapezoidal rule with extrapolation to infinity. |
| Pharmacokinetic Analysis: Dose-normalized Cmax | Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days) | The maximum dose-normalized plasma concentration (Cmax) will be obtained directly from the experimental data. |
| Pharmacokinetic Analysis: T1/2 | Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days) | Terminal half-life (T1/2) will be obtained from the terminal rate constant calculated by linear regression using at least 3 observations. |
| Pharmacokinetic Analysis: Total Body Clearance (CL) | Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days) | Total body clearance (CL), calculated by dividing the administered dose by the AUC with extrapolation to infinity. |
| Pharmacokinetic Analysis: Volume of Distribution | Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days) | Volume of distribution (both at steady state and based on the terminal phase) (Vss and Vz, respectively): Vss is an estimate that equals mean residence time times total body clearance. Vz, calculated dividing the administered dose by the product of the AUC with extrapolation to infinity by the terminal rate constant |
Countries
Spain
Participant flow
Recruitment details
14 patients were included and treated at 2 sites: 3 in Part A in Sequence 1 (S1 TR: ITZ+lurbinectedin in Cycle 1) and 11 in Part B, of them 5 in S1 and 6 in Sequence 2 (S2 RT: ITZ+lurbinectedin in Cycle 2). In Part A, all patients were assigned to S1 TR, while in Part B, patients were randomly assigned at a 1:1 ratio to S1 TR or S2 RT. Patients participated between 7Oct2020 and 3Mar2022 (last follow-up). The 1st dose of the 1st cycle on 15Oct2020. The last dose of the last cycle on 7Feb2022.
Participants by arm
| Arm | Count |
|---|---|
| Part A - S1 (TR) PART A The dose of lurbinectedin when given in combination with itraconazole for the initial three patients in Part A will be 0.8 mg/m². In Part A, all patients will receive itraconazole plus lurbinectedin in Cycle 1 and lurbinectedin alone in Cycles 2 and 3 (this last cycle being optional).
Sequence 1 (TR)
* Cycle 1: Itraconazole + lurbinectedin 0.8 mg/m²
* Cycle 2: Lurbinectedin alone 3.2 mg/m²
* Cycle 3: Lurbinectedin alone 3.2 mg/m² (optional)
Lurbinectedin alone: The dose of lurbinectedin during Parts A and B will be 3.2 mg/m² for all patients when administered without itraconazole.
Lurbinectedin+Itraconazole co-administration: The dose of lurbinectedin when given in combination with itraconazole for the initial three patients in Part A will be 0.8 mg/m², and in Part B is susceptible to be adjusted properly if deemed necessary based on exposure and safety experience in Part A | 3 |
| Part B - S1 (TR) PART B Randomization will apply for study Part B only. In Part B is susceptible to be adjusted properly if deemed necessary based on exposure and safety experience in Part A. In Part B, patients will be randomly assigned to the corresponding sequences.
Sequence 1 (TR)
* Cycle 1: Itraconazole + lurbinectedin 0.8 mg/m²
* Cycle 2: Lurbinectedin alone 3.2 mg/m²
* Cycle 3: Lurbinectedin alone 3.2 mg/m² (optional)
Lurbinectedin alone: The dose of lurbinectedin during Parts A and B will be 3.2 mg/m² for all patients when administered without itraconazole.
Lurbinectedin+Itraconazole co-administration: The dose of lurbinectedin when given in combination with itraconazole for the initial three patients in Part A will be 0.8 mg/m², and in Part B is susceptible to be adjusted properly if deemed necessary based on exposure and safety experience in Part A | 5 |
| Part B - S2 (RT) PART B Randomization will apply for study Part B only. In Part B is susceptible to be adjusted properly if deemed necessary based on exposure and safety experience in Part A. In Part B, patients will be randomly assigned to the corresponding sequences.
Sequence 2 (RT):
* Cycle 1: Lurbinectedin alone 3.2 mg/m²
* Cycle 2: Itraconazole + lurbinectedin 0.8 mg/m²
* Cycle 3: Lurbinectedin alone 3.2 mg/m² (optional) Lurbinectedin alone: The dose of lurbinectedin during Parts A and B will be 3.2 mg/m² for all patients when administered without itraconazole.
Lurbinectedin+Itraconazole co-administration: The dose of lurbinectedin when given in combination with itraconazole for the initial three patients in Part A will be 0.8 mg/m², and in Part B is susceptible to be adjusted properly if deemed necessary based on exposure and safety experience in Part A. | 6 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 |
| Overall Study | Compassionate use | 1 | 3 | 3 |
| Overall Study | Progressive disease | 2 | 0 | 3 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Part A - S1 (TR) | Part B - S1 (TR) | Part B - S2 (RT) | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 2 Participants | 2 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 3 Participants | 4 Participants | 8 Participants |
| Age, Continuous | 69 years | 64 years | 62 years | 63 years |
| ECOG PS 0 | 1 Participants | 4 Participants | 5 Participants | 10 Participants |
| ECOG PS 1 | 2 Participants | 1 Participants | 1 Participants | 4 Participants |
| Height | 165 cm | 163 cm | 166.5 cm | 165 cm |
| Number of prior chemotherapy lines | 2 Lines of chemotherapy | 3 Lines of chemotherapy | 5 Lines of chemotherapy | 4 Lines of chemotherapy |
| Number of prior lines | 4 lines | 3 lines | 6 lines | 4 lines |
| Number of sites at baseline | 4 sites | 3 sites | 2 sites | 3 sites |
| Primary tumor Colon adenocarcinoma | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Primary tumor Endometrial carcinoma | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Primary tumor Epidermoid carcinoma | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Primary tumor Leiomyosarcoma | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Primary tumor Lung | 0 Participants | 1 Participants | 2 Participants | 3 Participants |
| Primary tumor Mesothelioma | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Primary tumor Ovarian carcinoma | 1 Participants | 0 Participants | 3 Participants | 4 Participants |
| Primary tumor Pancreatobiliary adenocarcinoma | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Prior chemotherapy lines 2 lines | 2 Participants | 1 Participants | 0 Participants | 3 Participants |
| Prior chemotherapy lines 3 lines | 0 Participants | 2 Participants | 1 Participants | 3 Participants |
| Prior chemotherapy lines ≥4 lines | 1 Participants | 2 Participants | 5 Participants | 8 Participants |
| Prior lines 2 lines | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Prior lines 3 lines | 0 Participants | 3 Participants | 1 Participants | 4 Participants |
| Prior lines ≥4 lines | 2 Participants | 2 Participants | 5 Participants | 9 Participants |
| Prior radiotherapy | 1 Participants | 2 Participants | 3 Participants | 6 Participants |
| Prior surgery | 2 Participants | 3 Participants | 4 Participants | 9 Participants |
| Race/Ethnicity, Customized White | 3 Participants | 5 Participants | 6 Participants | 14 Participants |
| Region of Enrollment Spain | 3 participants | 5 participants | 6 participants | 14 participants |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 4 Participants | 9 Participants |
| Sex: Female, Male Male | 0 Participants | 3 Participants | 2 Participants | 5 Participants |
| Sites at baseline 1 | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Sites at baseline 2 | 1 Participants | 2 Participants | 2 Participants | 5 Participants |
| Sites at baseline 3 | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Sites at baseline >4 | 2 Participants | 2 Participants | 1 Participants | 5 Participants |
| Stage at diagnosis Early | 1 Participants | 1 Participants | 2 Participants | 4 Participants |
| Stage at diagnosis Locally advanced | 0 Participants | 1 Participants | 2 Participants | 3 Participants |
| Stage at diagnosis Metastatic | 2 Participants | 3 Participants | 2 Participants | 7 Participants |
| Time from diagnosis to first infusion | 2.6 years | 3.4 years | 3.5 years | 3.4 years |
| Weight | 58.9 kg | 66.6 kg | 69.5 kg | 67.5 kg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 13 | 1 / 14 |
| other Total, other adverse events | 12 / 13 | 13 / 14 |
| serious Total, serious adverse events | 4 / 13 | 5 / 14 |
Outcome results
Primary
Pharmacokinetic Analysis: Dose-adjusted AUC(0-∞)
The primary parameter of interest for the statistical analysis will be plasma dose adjusted AUC(0-∞)
Time frame: Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days)
Population: The pharmacokinetic analysis included data from only PK - evaluable patients from study Part B and the same study population was used to perform the statistical analysis in evaluating the ITZ - lurbinectedin drug-drug interaction. Part A was meant to ensure the adequacy of the dose of lurbinectedin (0.8 mg/m²) when given in combination with itraconazole, and patients (n=3) were not randomized for treatment sequence, so they were not included in the main analysis, as pre-specified in protocol.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ITZ+LRB | Pharmacokinetic Analysis: Dose-adjusted AUC(0-∞) | 288.55 μg·h/L/mg | Geometric Coefficient of Variation 73.9 |
| LRB Alone | Pharmacokinetic Analysis: Dose-adjusted AUC(0-∞) | 105.8 μg·h/L/mg | Geometric Coefficient of Variation 77.37 |
90% CI: [213.22, 348.86]ANOVA
Secondary
Pharmacokinetic Analysis: Dose-normalized AUC(0-t)
The dose-normalized area under the concentration-time curve (AUC) will be calculated using the linear-log trapezoidal rule with extrapolation to infinity.
Time frame: Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days)
Population: The pharmacokinetic analysis included data from only PK - evaluable patients from study Part B and the same study population was used to perform the statistical analysis in evaluating the ITZ - lurbinectedin drug-drug interaction
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ITZ+LRB | Pharmacokinetic Analysis: Dose-normalized AUC(0-t) | 244.77 μg·h/L/mg | Geometric Coefficient of Variation 91.89 |
| LRB Alone | Pharmacokinetic Analysis: Dose-normalized AUC(0-t) | 103.4 μg·h/L/mg | Geometric Coefficient of Variation 78.85 |
90% CI: [177.35, 316]ANOVA
Secondary
Pharmacokinetic Analysis: Dose-normalized Cmax
The maximum dose-normalized plasma concentration (Cmax) will be obtained directly from the experimental data.
Time frame: Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days)
Population: The pharmacokinetic analysis included data from only PK - evaluable patients from study Part B and the same study population was used to perform the statistical analysis in evaluating the ITZ - lurbinectedin drug-drug interaction
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ITZ+LRB | Pharmacokinetic Analysis: Dose-normalized Cmax | 25.91 μg/L/mg | Geometric Coefficient of Variation 53.15 |
| LRB Alone | Pharmacokinetic Analysis: Dose-normalized Cmax | 22.43 μg/L/mg | Geometric Coefficient of Variation 53.75 |
90% CI: [100.07, 133.33]ANOVA
Secondary
Pharmacokinetic Analysis: T1/2
Terminal half-life (T1/2) will be obtained from the terminal rate constant calculated by linear regression using at least 3 observations.
Time frame: Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days)
Population: The pharmacokinetic analysis included data from only PK - evaluable patients from study Part B and the same study population was used to perform the statistical analysis in evaluating the ITZ - lurbinectedin drug-drug interaction
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ITZ+LRB | Pharmacokinetic Analysis: T1/2 | 101.36 hours | Geometric Coefficient of Variation 61 |
| LRB Alone | Pharmacokinetic Analysis: T1/2 | 46.59 hours | Geometric Coefficient of Variation 17.12 |
90% CI: [151.81, 311.82]ANOVA
Secondary
Pharmacokinetic Analysis: Total Body Clearance (CL)
Total body clearance (CL), calculated by dividing the administered dose by the AUC with extrapolation to infinity.
Time frame: Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days)
Population: The pharmacokinetic analysis included data from only PK - evaluable patients from study Part B and the same study population was used to perform the statistical analysis in evaluating the ITZ - lurbinectedin drug-drug interaction
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ITZ+LRB | Pharmacokinetic Analysis: Total Body Clearance (CL) | 3.47 L/h | Geometric Coefficient of Variation 73.9 |
| LRB Alone | Pharmacokinetic Analysis: Total Body Clearance (CL) | 9.45 L/h | Geometric Coefficient of Variation 77.37 |
90% CI: [28.66, 46.9]ANOVA
Secondary
Pharmacokinetic Analysis: Volume of Distribution
Volume of distribution (both at steady state and based on the terminal phase) (Vss and Vz, respectively): Vss is an estimate that equals mean residence time times total body clearance. Vz, calculated dividing the administered dose by the product of the AUC with extrapolation to infinity by the terminal rate constant
Time frame: Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days)
Population: The pharmacokinetic analysis included data from only PK - evaluable patients from study Part B and the same study population was used to perform the statistical analysis in evaluating the ITZ - lurbinectedin drug-drug interaction
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ITZ+LRB | Pharmacokinetic Analysis: Volume of Distribution | 418.68 L | Geometric Coefficient of Variation 111.45 |
| LRB Alone | Pharmacokinetic Analysis: Volume of Distribution | 419.14 L | Geometric Coefficient of Variation 58.58 |
90% CI: [65.76, 151.74]ANOVA