Metastatic Urothelial Cancer
Conditions
Brief summary
This is a single arm open label multi-institutional phase II trial of olaparib monotherapy in subjects with metastatic urothelial cancer harboring somatic DNA damage response (DDR) alterations. The primary objective of the study is to estimate the objective response rate (per RECIST 1.1) to treatment with olaparib.
Interventions
DRUGOlaparib
1 cycle = 28 days. Subject's with calculated creatinine clearance (CrCl) of ≥ 40 mL/min will start at a dose of olaparib tablets of 300 mg twice a day. Subjects with a CrCl of \> 30 to \< 40 mL/min will start at a dose of olaparib tablets 200 mg twice a day.
Sponsors
Icahn School of Medicine at Mount Sinai
AstraZeneca
Matthew Galsky
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately. * Age ≥ 18 years at the time of consent. * ECOG Performance Status of ≤ 1 within 14 days prior to registration. Cisplatin-ineligible chemotherapy-naïve subjects (see inclusion criteria #8) may have an ECOG Performance Status of ≤ 2. * Histological or cytological evidence/confirmation of urothelial cancer. * Metastatic and/or unresectable (cT4b) urothelial cancer. * Metastatic disease evaluable on imaging studies. Subjects may have measurable disease according to RECIST 1.1 or bone-only disease within 30 days prior to registration. * NOTE: Bone-only subjects are eligible if their disease can be documented/ evaluated by bone scans, CT or MRI. Their disease will be assessed using MD Anderson criteria.34 * NOTE: Previously irradiated lesions are eligible as a target lesion only if there is documented progression of the lesion after irradiation. * Somatic alteration considered pathogenic/likely pathogenic in one of the following DDR genes as determined by genomic sequencing performed in a Clinical Laboratory Improvement Amendments (CLIA) laboratory. Somatic alterations will include nonsense, frameshift, splice-site or missense mutations or homozygous deletions. Subjects with alterations in DDR genes not included in the list below will be considered on a case by case basis after discussion with the sponsor-investigator(s). Subjects with germline alterations in DDR genes will be considered on a case by case basis and will be reviewed by the sponsor-investigator(s). At least 6 subjects will have BRCA or ATM alterations. * Nucleotide Excision Repair: ERCC2, ERCC3,ERCC4, ERCC5, ERCC6 * Homologous Recombination: BRCA1, RAD52, BRCA2, RAD54L, RAD50, NBN RAD51, MRE11A, RAD51B, RAD51D, RAD51C, CTIP * DNA Sensor: ATM, ATR, MDC1, ATRX, CHEK1, CHEK2 * Fanconi Anemia Pathway: PALB2, FANCE, BRIP1, FANCF, FANCA, FANCG FANCB, BLM, FANCC, FANCD2 * Base Excision Repair: XRCC2, XRCC3, XRCC4, XRCC5, XRCC6 * Other: MUTYH, RECQL4, POLQ, POLE, WRN * A subject with prior brain metastasis may be considered if they have completed their treatment for brain metastasis at least 4 weeks prior to study registration, have been off of corticosteroids for ≥ 2 weeks, and are asymptomatic * Subjects must have progressed despite at least 1 prior line of treatment for metastatic and/or unresectable urothelial cancer. However, cisplatin-ineligible (defined by a calculated creatinine clearance of \>30 but \< 60 mL/min OR CTCAE v4 Grade ≥ 2 audiometric hearing loss OR CTCAE v4 Grade ≥ 2 peripheral neuropathy OR ECOG PS = 2), and chemotherapy-naïve subjects are also eligible. * Prior cancer treatment (systemic therapy or radiation therapy) must be completed at least 3 weeks prior to registration and the subject must have recovered from all reversible acute toxic effects of the regimen (other than alopecia) to Grade ≤ 1 or baseline. * Demonstrate adequate organ function as defined in the table below. All screening labs to be obtained within 28 days prior to registration. * Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L * Hemoglobin (Hgb) ≥ 9 g/dL * Platelets ≥ 100 x 109/L * Calculated creatinine clearance ≥ 30 mL/min * Bilirubin ≤ 1.5 × upper limit of normal (ULN) * Aspartate aminotransferase (AST) ≤ 2.5 × ULN (or ≤ 5 × ULN if liver metastases) * Alanine aminotransferase (ALT) ≤ 2.5 × ULN (or ≤ 5 × ULN if liver metastases) * Female subjects must be postmenopausal or there must be evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 28 days of study treatment and confirmed prior to treatment on day 1. * Females of childbearing potential must be willing to abstain from heterosexual activity or to use 2 forms of highly effective methods of contraception from the time of informed consent until 90 days after treatment discontinuation. The two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method. Males must be willing to abstain from heterosexual activity or to use 2 forms of highly effective methods of contraception from the time of informed consent until 90 days after treatment discontinuation. * As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study * 15\. All subjects must have adequate archival tissue available prior to registration (i.e., at least 15 unstained slides or paraffin block). Archival tissue should represent invasive or metastatic urothelial cancer with a preference for metastatic tissue if available. Archival tissue should be identified at screening and shipped by C1D1. Subjects without adequate tissue may be considered on a case by case basis after discussion with the sponsor-investigator.
Exclusion criteria
* Active infection requiring systemic therapy. * Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study). * Known additional malignancy that is active and/or progressive requiring treatment; subjects with other malignancies that have been definitively treated and who have been rendered disease free will be eligible. * Prior treatment with a PARP inhibitor, including olaparib. * Treatment with any investigational drug within 30 days prior to registration. * Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). * Resting ECG with QTc \> 470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome. * Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks. * Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents. * Subjects with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of MDS/AML. * Major surgery within 2 weeks of starting study treatment and subjects must have recovered from any effects of any major surgery. * Subjects considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography (HRCT) scan, history of pneumonitis, or any psychiatric disorder that prohibits obtaining informed consent. * Subjects unable to swallow orally administered medication and subjects with gastrointestinal disorders likely to interfere with absorption of the study medication. * Immunocompromised subjects, e.g., subjects who are known to be serologically positive for human immunodeficiency virus (HIV). * Subjects with a known hypersensitivity to olaparib or any of the excipients of the product. * Subjects with known active hepatitis (i.e. Hepatitis B or C) due to risk of transmitting the infection through blood or other body fluids * Previous allogeneic bone marrow transplant or double umbilical cord blood transplantation (dUCBT)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | Up to a maximum of 17 months | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. ORR is defined as the proportion of all subjects with confirmed PR or CR according to RECIST 1.1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | Time of treatment start until the criteria for disease progression or death. Up to a maximum of 17 months. | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. PFS is defined as time from registration until disease progression met by RECIST 1.1 or death from any cause. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Time of treatment start until death or date of last contact, up to a maximum of 23 months. | Overall survival is defined as the time from treatment start until death or date of last contact. |
| Adverse Events | AE had been recorded from time of signed informed consent until 30 days after discontinuation of study drug(s) or until a new anti-cancer treatment starts, whichever occurs first, up to a maximum of 18 months. | Number of participants with treatment related adverse events are reported by CTCAEv4 term and grade. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Olaparib Monotherapy The starting dose of olaparib tablets will be dependent on the subject's calculated creatinine clearance (CrCl). Subjects with a CrCl of ≥ 40 mL/min will start at a dose of olaparib tablets of 300 mg twice a day. Subjects with a CrCl of \> 30 to \< 40 mL/min will start at a dose of olaparib tablets 200 mg twice a day.
Olaparib: 1 cycle = 28 days. Subject's with calculated creatinine clearance (CrCl) of ≥ 40 mL/min will start at a dose of olaparib tablets of 300 mg twice a day. Subjects with a CrCl of \> 30 to \< 40 mL/min will start at a dose of olaparib tablets 200 mg twice a day. | 19 |
| Total | 19 |
Baseline characteristics
| Characteristic | Olaparib Monotherapy |
|---|---|
| Age, Continuous | 66 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Prior Systemic Therapies | 2 Lines of therapy |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 16 Participants |
| Region of Enrollment United States | 19 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 13 / 19 |
| other Total, other adverse events | 18 / 19 |
| serious Total, serious adverse events | 11 / 19 |
Outcome results
Primary
Objective Response Rate (ORR)
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. ORR is defined as the proportion of all subjects with confirmed PR or CR according to RECIST 1.1.
Time frame: Up to a maximum of 17 months
Population: Out of 19 patients, four subjects were not evaluable for best response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Olaparib Monotherapy | Objective Response Rate (ORR) | 0 Percentage of participants |
Secondary
Progression-Free Survival (PFS)
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. PFS is defined as time from registration until disease progression met by RECIST 1.1 or death from any cause.
Time frame: Time of treatment start until the criteria for disease progression or death. Up to a maximum of 17 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Olaparib Monotherapy | Progression-Free Survival (PFS) | 1.9 Months |
Other Pre-specified
Adverse Events
Number of participants with treatment related adverse events are reported by CTCAEv4 term and grade.
Time frame: AE had been recorded from time of signed informed consent until 30 days after discontinuation of study drug(s) or until a new anti-cancer treatment starts, whichever occurs first, up to a maximum of 18 months.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Olaparib Monotherapy | Adverse Events | Sore throat | 1 Participants |
| Olaparib Monotherapy | Adverse Events | Chronic kidney disease | 1 Participants |
| Olaparib Monotherapy | Adverse Events | Creatinine increased | 2 Participants |
| Olaparib Monotherapy | Adverse Events | WBC count decreased | 1 Participants |
| Olaparib Monotherapy | Adverse Events | Lymphocyte count decreased | 2 Participants |
| Olaparib Monotherapy | Adverse Events | Neutrophil count decreased | 2 Participants |
| Olaparib Monotherapy | Adverse Events | Platelet count decreased | 3 Participants |
| Olaparib Monotherapy | Adverse Events | Anemia | 5 Participants |
| Olaparib Monotherapy | Adverse Events | Fatigue | 4 Participants |
| Olaparib Monotherapy | Adverse Events | Fever | 1 Participants |
| Olaparib Monotherapy | Adverse Events | Dizziness | 1 Participants |
| Olaparib Monotherapy | Adverse Events | Anorexia | 2 Participants |
| Olaparib Monotherapy | Adverse Events | Myalgia | 1 Participants |
| Olaparib Monotherapy | Adverse Events | Nausea | 4 Participants |
| Olaparib Monotherapy | Adverse Events | Vomiting | 3 Participants |
| Olaparib Monotherapy | Adverse Events | Diarrhea | 2 Participants |
| Olaparib Monotherapy | Adverse Events | Constipation | 1 Participants |
| Olaparib Monotherapy | Adverse Events | Abdominal pain | 1 Participants |
| Olaparib Monotherapy | Adverse Events | Allergic reaction | 1 Participants |
| Olaparib Monotherapy | Adverse Events | Confusion | 1 Participants |
| Olaparib Monotherapy | Adverse Events | Papulopustular rash | 1 Participants |
| Olaparib Monotherapy | Adverse Events | Skin disorders, other | 1 Participants |
Other Pre-specified
Overall Survival (OS)
Overall survival is defined as the time from treatment start until death or date of last contact.
Time frame: Time of treatment start until death or date of last contact, up to a maximum of 23 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Olaparib Monotherapy | Overall Survival (OS) | 9.5 Months |