Appendiceal Cancer, Appendiceal Neoplasms, Breast Cancer, Cholangiocarcinoma, Colorectal Cancer, Colorectal Neoplasms, Gynecologic Cancer, Gynecologic Neoplasms, Ovarian Cancer, Ovarian Neoplasms, Peritoneal Carcinomatosis, Peritoneal Neoplasms
Conditions
Keywords
Taxol, Tasigna, Peritoneal Carcinomatosis Index (PCI), Cytoreductive Surgery (CRS), Unresectable, Percent necrosis, Ki-67, Peritoneal Metastasis, Progression Free Survival
Brief summary
Background: Tumors that have spread to the lining of the abdomen from other cancers, such as cancer of the appendix, colon, or ovary, are called peritoneal carcinomatosis. In most cases, outcomes are poor. Researchers want to test a new treatment. Objective: To learn if the combination of oral nilotinib plus paclitaxel given by intravenous (IV) and directly into the abdomen can reduce tumors enough for people to have surgery. Eligibility: Adults aged 18 and older with peritoneal carcinomatosis that is too widespread for surgery. Design: Participants will be screened with: Physical exam Medical history Blood and urine tests Electrocardiogram Laparoscopy. They will get general anesthesia. Small cuts will be made in their abdomen. Tissue and fluid samples will be taken. Surveys about their health Computed tomography (CT) scans of their torso Participants will have up to 4 more laparoscopies. During the first procedure, a port will be placed under the skin of their abdomen (an intraperitoneal (IP) port). It will be attached to a catheter that is placed in their abdomen. Participants will get treatment in 3-week cycles, for 3 or 6 cycles. They will take nilotinib by mouth twice daily. They will get paclitaxel by IP port (once per cycle) and by IV (twice per cycle). After cycles 3 and 6, they will have a laparoscopy and CT scans. Then they may take nilotinib and get IV paclitaxel for up to 1 year. At study visits, participants will repeat some screening tests. About 6 weeks after treatment ends and then every 3 months for 3 years, participants will have follow-up visits at National Institutes of Health (NIH) or with their local doctor.
Detailed description
Background: * Peritoneal carcinomatosis is uniformly fatal if untreated; despite advances in systemic chemotherapy, cytoreductive surgery, and intraperitoneal chemotherapy, survival remains poor for the majority of patients * The combination of oral nilotinib and intravenous paclitaxel has demonstrated pre-clinical and clinical synergism in the treatment of solid tumors, with an ongoing Phase I trial at the National Institutes of Health (NIH) * The synergy of oral nilotinib with intraperitoneal paclitaxel remains to be characterized * This study involves the combination of intravenous and intraperitoneal paclitaxel and oral nilotinib for unresectable peritoneal carcinomatosis from colorectal, appendiceal, small bowel, gastric, cholangiocarcinoma, breast, ovarian, or other gynecologic primary histologies. Objective: -To evaluate efficacy of bidirectional chemotherapy using intraperitoneal and intravenous paclitaxel and oral nilotinib by calculating the rate of downstaging of peritoneal disease burden to become resectable, based on Peritoneal Carcinomatosis Index (PCI) Eligibility: * Participants \>= 18 years of age with histologically confirmed peritoneal carcinomatosis of colorectal, appendiceal, small bowel, gastric, cholangiocarcinoma, breast, ovarian, or other gynecologic primary histology * Demonstrated resistance or lack of response to at least one line of already approved and available systemic chemotherapy * No history of allergic reactions attributed to compounds of similar chemical or biologic composition to study drugs * No intraperitoneal chemotherapy within the last six months * Deemed unable to undergo complete cytoreduction Design: * Phase II open-label, non-randomized study * After confirmation of eligibility, at the time of diagnostic laparoscopy, biopsies will be taken, and an intraperitoneal catheter will be placed for subsequent chemotherapy administration * Up to 6 cycles will be planned, with restaging laparoscopy and biopsies after Cycles 3 and 6
Interventions
DRUGPaclitaxel
Paclitaxel: Intraperitoneal (IP) paclitaxel will be dosed at 60 mg/m\^2 to be infused over 1 hour on Day 1 of each 3-week cycle; participants with unresectable, but stable or responding disease after C1 through C3 will dose increase IP paclitaxel to 80 mg/m2 for Cycles 4-6. Intravenous (IV) paclitaxel will be infused over 1 hour on Day 2 of the first week of Cycle 1, followed by Day 1 of the subsequent treatment weeks; IV paclitaxel will be dosed at 60 mg/m2 for Week 1 of Cycle 1 and, if tolerated, at 80 mg/m2 for subsequent treatments.
DRUGNilotinib
Oral nilotinib will be dosed at 300 mg twice daily. Nilotinib will be administered continually from the loading dose (Day -4) leading up to laparoscopy #2 onward.
DIAGNOSTIC_TESTECG
Screening, Week -1, Cycle 1 and 4 Day 1 (±3 days at start of cycle), Cycle 2 and 5 Day 1 (±3 days at start of cycle), Cycle 3 and 6 Day 1 (±3 days at start of cycle) and 4-8 Weeks post-therapy (±2 weeks).
DIAGNOSTIC_TESTCT Scan CAP
Screening, Cycle 3 and 6 Day 1, Week 6, and every 3 months (± 2 weeks) for up to 3 years total.
PROCEDURELaparoscopy
Screening, Day 0, Week -1, and Cycle 3 and 6, Week 3.
PROCEDUREPeritoneal biopsies + ascites washings
Screening (intra-op), Week -1, Day 0 (intra-op), and on treatment (± 1 day), Cycle 3 and 6, Week 3 (intra-op). Biopsy only done if deemed eligible per laparoscopy (only performed during laparoscopy).
Sponsors
National Cancer Institute (NCI)
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
* INCLUSION CRITERIA: In order to be eligible to participate in this study, an individual must meet all of the following criteria. * Histological confirmation of peritoneal carcinomatosis from colorectal, appendiceal, small bowel, gastric, cholangiocarcinoma, breast, ovarian, or other gynecologic (i.e., endometrial, fallopian tube, primary peritoneal, cervical) primary by the Laboratory of Pathology, national Cancer Institute (NCI). * Participants must have been treated with at least one line of approved systemic chemotherapy, with demonstrated resistance or lack of response * Measurable or evaluable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. criteria and/or by Peritoneal Carcinomatosis Index (PCI) * Participants must be assessed to not be candidates for cytoreductive surgery, with laparoscopically assessed Peritoneal Cancer Index (PCI) score thresholds as indicated below: --Primary Histology PCI Cutoff for Eligibility * Gastric Total Score \>= 10 (out of 39 possible points) * Others Total Score \>= 20 (out of 39 possible points) * Any Jejunoileal Score \>= 4 (out of 12 possible points) * Age \>= 18 years * Eastern Cooperative Oncology Group (ECOG) performance status \<= 2 (Karnofsky \>= 60%). * Participants must have adequate organ and marrow function as defined below: * Absolute neutrophil count \>= 1,000/mcL * Platelets \>= 100,000/mcL * Total bilirubin within \<= 1.5x institutional upper limit of normal (ULN) * Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT)/Alanine aminotransferase (ALT) serum glutamic pyruvic transaminase (SGPT) \<= 3x institutional ULN, or \<= 5.0x ULN in participants with liver metastases (only) * Serum potassium and magnesium greater than institutional lower limit of normal * Creatinine \<= 1.5 mg/dL or creatinine clearance \>= 60 mL/min/1.73 m\^2 for participants with creatinine levels above institutional normal calculated using estimated glomerular filtration rate (eGFR) * Nursing (including breastfeeding) participant must agree to discontinue nursing. * Individuals of child-bearing potential (IOCBP) must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and for 90 days after last study treatment. Should an individual of child-bearing potential suspect to be pregnant while participating in this study, the individual should inform the treating physician immediately. * Ability of participant to understand and the willingness to sign a written informed consent document. * Participants must agree to co-enrollment on the tissue collection protocol 13C0176, Tumor, Normal Tissue and Specimens from Patients Undergoing Evaluation or Surgical Resection of Solid Tumors
Exclusion criteria
An individual who meets any of the following criteria will be excluded from participation in this study. * Participants who are receiving any other investigational agents or who have received an investigational agent within 30 days prior to the start of study treatment. * Participants with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to study drugs. * Participants who have received systemic (i.e., oral or intravenous) chemotherapy or other anti-cancer therapy (i.e., immunotherapy) within either 5 half-lives or within 30 days of the last dose of individual agent(s) administered prior to the start of study treatment, whichever is shorter. * Participants who have undergone major abdominal surgery within the last 12 weeks prior to the start of study treatment. Note: Exclusion of participants who have undergone major abdominal surgery within the last 12 weeks prior to start of study treatment is to allow for scar tissue formation from that surgery to stabilize. Participant ECOG performance status will be checked to account for prolonged or difficult recoveries from other types of major surgery that would appropriately influence eligibility assessment. * Participants who have received previous intraperitoneal chemotherapy within the last 6 months prior to the start of study treatment * Participants requiring the use of drugs known to prolong the QT interval or known to strongly inhibit cytochrome P450 3A4 (CYP3A4), cytochrome P450 CYP (2C8). Participants on such agents at the time of screening are permitted on study if an alternative that does not have the same pharmacokinetic interactions can be found. * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Note: No subject will be excluded based on a social situation prior to consultation with the Department of Social Work. * Pregnant individuals are excluded from this study. * Participants with human immunodeficiency virus (HIV) who have detectable viral load, or whose Antiretroviral therapy (ART) contains corrected QT interval (QTc) Prolonging Medications or CYP3A4 Inhibitors regardless of viral load. (NOTE: Participants with HIV who have an undetectable viral load and have been on stable doses of ART that does not prolong the QT interval or is a strong CYP3A4, 2C8 inhibitor are eligible). * QT corrected for heart rate by Fridericia's cube root formula (QTcF) interval of \>= 450 msec at study entry, or congenital long QT syndrome. * More than 3 liters of ascites present at initial laparoscopy, or history of more than two therapeutic paracentesis procedures, each yielding at least 1.5 liters of fluid, in the 30 days prior to initial laparoscopy, or confirmation of predominantly mucinous ascites at the time of screening laparoscopy. * Advanced hepatic failure, as indicated by Child-Pugh Class C cirrhosis. * Sensory/motor neuropathy \>= Grade 2
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants Who Are Successfully Down Staged to Resectable Based on Peritoneal Carcinomatosis Index (PCI) and Principal Investigator (PI) Discretion Reported Along With a 95% Confidence Interval | Participants were followed from baseline (within 6 weeks prior to the start of treatment), and every 9 weeks during treatment through study completion for 27 months, 14 days | We calculated the rate of downstaging of peritoneal disease burden to become resectable based on PCI score of initial and subsequent laparoscopy, or magnetic resonance imaging and/or computed tomography imaging if laparoscopy is not planned. Disease burden will be considered stable when PCI score at laparoscopy (lap) #3 is \< 4 points higher or lower compared to PCI score at lap #2. Complete Response is PCI≤ 5 with negative histology of at least 3 peritoneal biopsies of suspect nodules and washings with negative cytology. Partial Response (PR) is at least 4 points decrease in PCI. Progressive Disease (PD) has at least 4 points increase in PCI. Stable Disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the PCI. To document PCI scoring for each participant, the rubric will be completed following each laparoscopy. The PCI is scaled from 0-39, with higher scores indicating higher disease burden and worse prognosis. |
| Proportion of Participants Who Are Successfully Down-staged to Resectable by Use of Chemotherapy Reported Along With a 95% Confidence Interval. | Baseline, every 9 weeks during treatment, and then every 3 months, up to 2 years | The proportion of participants who are successfully down-staged to resectable by use of chemotherapy will be reported along with a 95% confidence interval. This outcome measure evaluates how many participants with initially inoperable (unresectable) peritoneal carcinomatosis became eligible for surgery after receiving bidirectional chemotherapy (intravenous and intraperitoneal paclitaxel and oral nilotinib). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Participants were followed from time of initiation of study treatment to death or last follow-up through study completion for 27 months, 14 days | OS is defined as the time from the start of treatment until time of death from any cause, for up to 3 years after completion of therapy. OS will be reported using the Kaplan-Meier method, along with a 95% confidence interval. |
| Percent Probability of Peritoneal Progression-free Survival (pPFS) | From baseline, at peritoneal disease relapse from Complete Response (CR) or peritoneal disease progression, and after completion of therapy up to a percent probability of PFS at 12 months | Percent pPFS will be reported using the Kaplan-Meier method, along with a 95% confidence interval for each histology. PFS is defined as the duration of time from the start of the treatment until time of peritoneal disease relapse from Complete Response (CR) or peritoneal disease progression, or death, whichever comes first, and after completion of therapy. Response was assessed by the Peritoneal Carcinomatosis Index (PCI) and the Response Evaluation Criteria in Solid Tumors (RECIST). Disease relapse is CR is PCI≤ 5 with negative histology of at least 3 peritoneal biopsies of suspect nodules and washings with negative cytology. Disease progression is at least 4 points increase in PCI. The appearance of one or more new lesions is also considered progressions. The Kaplan-Meier method calculates a survival function S(t), which represents the probability of "surviving" (remaining event-free) beyond time t. It is not calculated directly as a percentage. |
| Number of Grades 3, 4, and/or 5 Serious and/or Non-serious Toxicities by Type Assessed Using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 | Day-4 through completion of surveillance post-treatment, up to 2 years. | Safety will be assessed by analyzing the type, grade and frequency of toxicities. Adverse events (AEs) will be assessed using CTCAE v.5.0. A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe. Grade 4 is life-threatening. Grade 5 is death related to adverse event. |
| Participants Quality of Life (QOL) Using the Functional Assessment of Cancer Therapy - Colorectal (FACT-C) Instrument | Participants were followed from baseline (within 6 weeks prior to start of treatment), and immediately prior to Cycle 3 (one cycle is 21 days) and Cycle 6 and in follow-up, up to 8 weeks post-treatment | Outcomes from QOL comparing results before to after treatment: Quality of life is assessed using the Functional Assessment of Cancer Therapy - Colorectal (FACT-C) questionnaire, a validated instrument that measures health-related quality of life. The FACT-C consists of the following subscales: Physical Well-Being (PWB): 7 items; score range 0-28, Social/Family Well-Being (SWB): 7 items; score range 0-28, Emotional Well-Being (EWB): 6 items; score range 0-24, Functional Well-Being (FWB): 7 items; score range 0-28, Colorectal Cancer Subscale (CCS):9 items; score range 0-36.The FACT-C total score is derived by summing all five subscale scores. Total score range: 0-144. For all subscales and the total score, higher values represent better quality of life and lower values represent worse quality of life. Questionnaires are administered at baseline, immediately prior to treatment Cycles 3 and 6, and at follow-up visits. A single value (average) was calculated for "during treatment immediate |
| Median Peritoneal Progression-free Survival (pPFS) | Baseline, at peritoneal disease relapse from Complete Response (CR) or peritoneal disease progression, and after completion of therapy, a median of 5.04 months | Kaplan-Meier method will be used to evaluate peritoneal progression-free survival (pPFS). Median peritoneal progression-free survival (pPFS) was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) and will be reported along with a 95% two-sided confidence interval. Progressive Disease is at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on available studies. The appearance of one or more new lesions is also considered progression. |
| Percentage of Participants With a Clinicopathologic Response to Therapy by Response Evaluation Criteria in Solid Tumor (RECIST)v 1.1 Reported With a 95% Confidence Interval | Participants were followed from baseline, every 9 weeks during treatment, and then every 3 months through study completion for 27 months, 14 days | The percentage of participants with a clinicopathologic response will be reported for all participants along with a 95% confidence interval. Complete Response (CR) is disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm. Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD) is at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on available studies. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study. |
| Median Overall Survival (OS) | From time of initiation of study treatment to death or last follow-up, a median of 5.60 months | Kaplan-Meier method will be used to evaluate median overall OS and will be reported with a 95% confidence interval. Overall survival (OS) is defined as the time from the start of the treatment until time of death from any cause, for up to 3 years after completion of therapy, assessed every 3 months (±2 weeks). |
| Percentage of Participants Who Become Resectable by Individual Histologies | Baseline, at peritoneal disease relapse from complete response (CR) or peritoneal disease progression, and after completion of therapy, up to 2 years | The percentage of participants who become resectable will be evaluated by individual histologies. |
| Participants Quality of Life (QOL) Using the EuroQoL 5-Dimension 5-Level (EQ-5D-5L) Questionnaire | Participants were followed from baseline (within 6 weeks prior to the start of treatment), during treatment immediately prior to Cycles 3 and 6, and after treatment (Follow-up at 4-8 weeks post-treatment) through study completion for 27 months, 14 days | Outcomes from QOL using the EuroQoL 5-Dimension 5-Level (EQ-5D-5L) questionnaire comparing results before to after treatment: physical and mental health-related quality of life will be reported. The EQ-5D-5L questionnaire assesses participants' physical and mental health-related quality of life (QOL). Questionnaires will be provided to the participants in an electronic application-based format to be filled out at baseline, and immediately prior to Cycles 3 and 6 and in follow-up. An index score of 100 is considered perfect health with no problems in any dimension. A score of 0.0 would be dead. A single value (average) was calculated for "during treatment immediately prior to Cycles 3 and Cycle 6". |
| Clinicopathologic Response to Therapy by Peritoneal Carcinomatosis Index (PCI) Reported for All Participants Along With a 95% Confidence Interval | Baseline, every 9 weeks during treatment, and then every 3 months for 2 years | Clinicopathologic response by PCI is reported with a 95% confidence interval. Complete Response (CR) is PCI ≤ 5 with negative histology of at least 3 peritoneal biopsies of suspect nodules and washings with negative cytology. Partial Response (PR) is at least 4 points decrease in PCI. Progressive Disease (PD) is at least 4 points increase in PCI. The appearance of one or more new lesions is also considered progression. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the PCI. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORAndrew M Blakely, M.D.
National Cancer Institute (NCI)
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 6 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants |
| Age, Continuous | 58.095 years STANDARD_DEVIATION 9.032 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 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 | 2 Participants |
| Race (NIH/OMB) White | 14 Participants |
| Region of Enrollment Canada | 1 participants |
| Region of Enrollment United States | 12 participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 6 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 | 4 / 4 | 0 / 1 | 1 / 1 | 1 / 1 |
| other Total, other adverse events | 4 / 4 | 1 / 1 | 1 / 1 | 1 / 1 |
| serious Total, serious adverse events | 2 / 4 | 0 / 1 | 1 / 1 | 0 / 1 |
Outcome results
None listed