Rectal Cancer
Conditions
Keywords
rectal cancer, colorectal cancer, locally advanced rectal cancer, locally advanced rectal cancer (resectable), locally advanced rectal cancer (non-resectable), chemoradiotherapy, nanopharmaceutical, CLRX101, camptothecin, capecitabine
Brief summary
This trial will enroll patients with locally advanced rectal cancer (resectable and non-resectable).The phase Ib dose escalation portion of trial is designed to determine the maximum tolerated dose (MTD) of CRLX101 when combined with standard neoadjuvant therapies capecitabine (Cape) and radiation therapy (XRT). CRLX101 is a nanopharmaceutical (NP) formulation of camptothecin. These results will determine the recommended phase II dose (RP2D) for CRLX101 in this setting. The phase II portion of the trial is designed to evaluate the efficacy and safety of CRLX101 at the RP2D, when combined with capecitabine and radiation therapy prior to surgery.
Detailed description
This is an open label, single-arm, multi-center, Phase Ib/II study designed to evaluate CRLX101, which is a NP formulation of camptothecin, dosed in combination with capecitabine and radiation therapy in patients with advanced rectal carcinoma. The purpose of the Phase Ib portion of this study is to identify the MTD of CRLX101 when added to standard neoadjuvant chemo-radiotherapy. The MTD will be based on the rate of dose-limiting toxicity (DLT) in Phase Ib, and will be assessed via NCI's CTCAE v4.0 toxicity criteria. The MTD will be assigned as the RP2D in this trial. If CRLX101 can be safely administered in combination with capecitabine and radiation at doses \>/= 9 mg/m\^2 IV in the Phase Ib study, then the trial will proceed to Phase II. Patients in the Phase Ib study will be included in the Phase II outcome analyses when applicable. The phase II study is designed to evaluate the efficacy of this regimen by assessing the rate of pathological complete response (pCR) while monitoring safety and tolerability. We anticipate accrual of up to 25 patients per year for the Phase II study, with a slightly faster accrual of 2-3 patients per month for Phase Ib given the broader inclusion criteria. During Phase Ib, we will evaluate the safety and determine the MTD/RP2D of CRLX101 + capecitabine (Cape) and radiation therapy (XRT) in patients with rectal cancer using the traditional 3+3 dose escalation design. Adverse events (AEs) will be evaluated via the CTCAE version 4.0. Patients in Phase Ib will also be followed for pathological response if they have resectable disease. If CRLX101 can be safely administered in combination with capecitabine and radiation at doses \>/=9 mg/m\^2 IV in the Phase Ib study, then the trial will proceed to Phase II with a primary objective of estimating the rate of pCR. Non-metastatic patients with resectable disease and treated at the MTD/RP2D in Phase Ib will be included in the Phase II study population. In Phase II, CRLX101 will be administered at the RP2D in combination with capecitabine and radiation in patients with locally advanced rectal cancer for a total of 5-6 weeks, depending on the total radiation dose. A total of 3 doses of CRLX101 will be administered every other week. Surgery will take place at least 6 weeks after the completion of chemoradiotherapy. For our non-metastatic Phase I patients and our Phase II population, postoperative adjuvant therapy is indicated regardless of whether a pCR is achieved or not. While there are a number of regimens used in the adjuvant setting, national guidelines do not specify one of these regimens over the other. Given the consistent application of adjuvant therapies in this population, we also plan to follow Phase II patients for both disease free survival (DFS) and overall survival (OS).
Interventions
DRUGCRLX101
CRLX101 is an experimental nanoparticle formulation of the anticancer agent camptothecin manufactured by Cerulean Pharma Inc..
DRUGCapecitabine
Capecitabine is an oral fluoropyrimidine pro-drug, metabolically converted to 5-fluorouracil after administration. It is indicated as adjuvant treatment in patients with stage III colorectal cancer (Dukes' C colon cancer), and as first-line treatment of metastatic colorectal cancer.
RADIATIONRadiotherapy
This protocol allows physician discretion as to the use of Intensity Modulated Radiation Therapy (IMRT) or 3D conformal planning techniques. Radiation begins on Day1 of neoadjuvant chemotherapy and continues for 28 (if \<T4) or 30 (T4 disease) consecutive weekdays. Patient will receive 1.8 Gy daily fractions of radiotherapy without a break except for weekends and holidays. Dose is to be prescribed to an isodose surface that encompasses the planning target volume (PTV) and that satisfies the dose uniformity guidelines below. The minimum dose to PTV 1 and PTV 2 shall be no less than 95% of the protocol specified dose for that volume.
PROCEDURESurgery
Surgery will take place at least 6 weeks post completion of chemoradiotherapy in patients with resectable disease; tissue from surgical resection will be preserved for correlative studies in those patients who do not achieve a pCR.
Sponsors
Cerulean Pharma Inc.
UNC Lineberger Comprehensive Cancer Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Eastern Cooperative Oncology Group (ECOG) performance score ≤ 2 2. Phase Ib and II: surgical candidates, with moderate to high-risk pathologically-confirmed rectal cancer (Tumor (T) and Nodal (N) stage cT3-4N0 or cT1-4N+); clinical staging by endoscopic ultrasound (EUS) or magnetic resonance imaging (MRI) is permitted. Phase Ib only: * Patients with metastatic rectal cancer are allowed if their primary site meets other eligibility criteria and chemoradiotherapy is recommended as initial therapy for symptom palliation by the multidisciplinary treating team * Patients with locally advanced unresectable rectal cancer are allow provided: * There is no evidence of recto-vaginal, recto-vesicular, recto-intestinal fistulization * Standard dose and schedule chemoradiotherapy is recommended as initial therapy by the multidisciplinary treating team 3. Age ≥18 years old 4. Women of childbearing potential (WOCBP) must have negative pregnancy test within 7 days prior to D1 of treatment 5. Recommendation to undergo concurrent chemoradiation, as determined by the treating physician 6. Ability to swallow oral medications 7. As determined by the enrolling physician or protocol designee, ability of the patient to understand and comply with study procedures for the entire length of the study 8. Informed consent reviewed and signed
Exclusion criteria
Patients meeting any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) of CRLX101 When Added to Standard Neoadjuvant Chemoradiotherapy Consisting of Capecitabine + Radiotherapy in Locally Advanced Rectal Cancer | 12 weeks | The MTD is the highest dose of CRLX101 at which ≤1 out of 6 patients had a dose limiting toxicity (DLT) using CTCAE v4.0 toxicity criteria. DLTs include Grade (G) \>3 neutropenia for ≥7 days; G 3 or 4 neutropenia with fever; G 4 anemia not related to cancer-associated bleeding; G 4 thrombocytopenia or G 3 with clinically significant bleeding; G ≥3 nausea or vomiting \>48 hours despite anti-emetics; G 2 cystitis not resolved within 14 days; second G 2 cystitis; G 3 or 4 cystitis; diarrhea requiring dose reduction; Any other non-hematologic toxicity G ≥3 requiring a dose reduction (G ≥3 infusion-related reactions were not a DLT unless they recur despite slowing down the infusion); Other CRLX101 related treatment emergent adverse effect (TEAE) that requires patient withdrawal prior to completing all doses; Radiotherapy interruption due to TEAEs ≥5 days; or Dose interruption or reduction of capecitabine due to TEAE that results in \<50% of the scheduled capecitabine dose for entire course |
| Pathological Complete Response (pCR) Rate | 12 weeks | Primary Objective Phase II: Pathological response will be made based on microscopic assessment of the surgical specimen at the primary treatment site. A pCR must include no gross or microscopic tumor identified anywhere within the surgical specimen. This must include:No evidence of malignant cells in the primary tumor specimen and No lymph nodes that contain tumor. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease-free Survival (DFS) Rate | An average of 2.6 years (full range 2.1 to 3.1 years) | Phase II only - DFS will be defined as the time from surgical resection until disease recurrence or death as a result of any cause, reported as the count of participants still alive without recurrence at the end of study follow-up. |
| Overall Survival (OS) Rate | an average of 2.6 years (full range 2.1 to 3.1 years) | Phase II only - OS is defined as the time from surgical resection until death reported as the count of participants still alive at the end of study follow-up. |
| Pathological Response Rate | 12 weeks | Pathologic response will be made based on microscopic assessment of the surgical specimen at the primary treatment site, including regional nodes and any peritumoral satellite nodules in the specimen, and categorized as outlined below as per the American Joint Committee on Cancer (AJCC) Cancer Staging Manual 7th edition.Determination of pathological response will be reported by the local pathologist. * Pathologic Complete Response (pCR): No gross or microscopic tumor identified anywhere within the surgical specimen. This must include: No evidence of malignant cells in the primary tumor specimen and No lymph nodes that contain tumor. * Moderate response: Single cells or small groups of cancer cells * Minimal response: Residual cancer outgrown by fibrosis * Poor response:Minimal or no tumor kill; extensive residual cancer |
| Overall Survival (OS) Based on Pathological Complete Response (pCR). | an average of 2.6 years (full range 2.1 to 3.1 years) | Phase II only - a comparison of OS for patients who achieve pCR and those who do not. OS is defined as the time from surgical resection until death reported as the count of participants still alive at the end of study follow-up. |
| Disease-free Survival (DFS) Rate Based on Pathological Complete Response (pCR). | an average of 2.6 years (full range 2.1 to 3.1 years) | Phase II only - a comparison of DFS for patients who achieve pCR and those who do not. DFS will be defined as the time from surgical resection until disease recurrence or death as a result of any cause, reported as the count of participants still alive without recurrence at the end of study follow-up. |
| Number of Participants With Grade 3 or Higher, Treatment-related Toxicities | 12 weeks | Toxicity profile of CRLX101 when combined with capecitabine + radiotherapy to treat patients with locally advanced rectal cancer. Phase Ib and Phase II - Safety is the reported adverse event (AE) profile characterized by NCI CTCAE v4.0. The profile was limited to grade 3 or higher, treatment related AEs. |
Countries
United States
Participant flow
Recruitment details
Patients were recruited from 5 medical institutions between December 2013 and September 2016
Pre-assignment details
A total of 39 patients were consented to this study; 4 patients were found ineligible, 3 withdrew prior to treatment, leaving 32 patients who went on study.
Participants by arm
| Arm | Count |
|---|---|
| Cohort A, Phase Ib, Dose Level 1 CRLX101 12mg/ m\^2 , via intravenous catheter (IV), on Monday, every other week for the first five weeks of chemoradiation.
Capecitabine 825mg/ m\^2 by mouth two times a day (PO BID), Monday through Friday (M-F) XRT 180 centigray (cGy)/day, M-F for 6 weeks | 3 |
| Cohort A, Phase Ib, Dose Level 2 CRLX101 15mg/ m\^2 , via intravenous catheter (IV), on Monday, every other week for the first five weeks of chemoradiation.
Capecitabine 825mg/ m\^2 PO BID, M-F XRT 180 cGy/day, M-F for 6 weeks | 6 |
| Cohort A, Phase II, Dose Level 2 CRLX101 15mg/ m\^2 , via intravenous catheter (IV), on Monday, every other week for the first five weeks of chemoradiation.
Capecitabine 825mg/ m\^2 PO BID, M-F XRT 180 cGy/day, M-F for 6 weeks | 14 |
| Cohort B, Phase Ib, Dose Level 1, Weekly CRLX101 12mg/ m\^2 , via intravenous catheter (IV), on Monday, every week for the first five weeks of chemoradiation.
Capecitabine 825mg/ m\^2 PO BID, M-F XRT 180 cGy/day, M-F for 6 weeks | 3 |
| Cohort B, Phase Ib, Dose Level 2, Weekly CRLX101 15mg/ m\^2 , via intravenous catheter (IV), on Monday, every week for the first five weeks of chemoradiation.
Capecitabine 825mg/ m\^2 PO BID, M-F XRT 180 cGy/day, M-F for 6 weeks | 6 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Cohort A, Phase Ib, Dose Level 1 | Cohort A, Phase Ib, Dose Level 2 | Cohort A, Phase II, Dose Level 2 | Cohort B, Phase Ib, Dose Level 1, Weekly | Cohort B, Phase Ib, Dose Level 2, Weekly | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 4 Participants | 14 Participants | 3 Participants | 5 Participants | 28 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 3 Participants | 0 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 3 Participants | 5 Participants | 11 Participants | 3 Participants | 4 Participants | 26 Participants |
| Region of Enrollment United States | 3 Participants | 6 Participants | 14 Participants | 3 Participants | 6 Participants | 32 Participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 4 Participants | 0 Participants | 3 Participants | 10 Participants |
| Sex: Female, Male Male | 1 Participants | 5 Participants | 10 Participants | 3 Participants | 3 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 6 | 0 / 14 | 0 / 3 | 0 / 6 |
| other Total, other adverse events | 3 / 3 | 6 / 6 | 14 / 14 | 3 / 3 | 6 / 6 |
| serious Total, serious adverse events | 0 / 3 | 0 / 6 | 1 / 14 | 0 / 3 | 0 / 6 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) of CRLX101 When Added to Standard Neoadjuvant Chemoradiotherapy Consisting of Capecitabine + Radiotherapy in Locally Advanced Rectal Cancer
The MTD is the highest dose of CRLX101 at which ≤1 out of 6 patients had a dose limiting toxicity (DLT) using CTCAE v4.0 toxicity criteria. DLTs include Grade (G) \>3 neutropenia for ≥7 days; G 3 or 4 neutropenia with fever; G 4 anemia not related to cancer-associated bleeding; G 4 thrombocytopenia or G 3 with clinically significant bleeding; G ≥3 nausea or vomiting \>48 hours despite anti-emetics; G 2 cystitis not resolved within 14 days; second G 2 cystitis; G 3 or 4 cystitis; diarrhea requiring dose reduction; Any other non-hematologic toxicity G ≥3 requiring a dose reduction (G ≥3 infusion-related reactions were not a DLT unless they recur despite slowing down the infusion); Other CRLX101 related treatment emergent adverse effect (TEAE) that requires patient withdrawal prior to completing all doses; Radiotherapy interruption due to TEAEs ≥5 days; or Dose interruption or reduction of capecitabine due to TEAE that results in \<50% of the scheduled capecitabine dose for entire course
Time frame: 12 weeks
Population: Since this objective applies only to Phase Ib patients, the Phase II cohort patients were not included
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation Phase Ib | Maximum Tolerated Dose (MTD) of CRLX101 When Added to Standard Neoadjuvant Chemoradiotherapy Consisting of Capecitabine + Radiotherapy in Locally Advanced Rectal Cancer | 15 mg/m^2 every other week |
Primary
Pathological Complete Response (pCR) Rate
Primary Objective Phase II: Pathological response will be made based on microscopic assessment of the surgical specimen at the primary treatment site. A pCR must include no gross or microscopic tumor identified anywhere within the surgical specimen. This must include:No evidence of malignant cells in the primary tumor specimen and No lymph nodes that contain tumor.
Time frame: 12 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation Phase Ib | Pathological Complete Response (pCR) Rate | 19 percentage of participants with pCR |
Secondary
Disease-free Survival (DFS) Rate
Phase II only - DFS will be defined as the time from surgical resection until disease recurrence or death as a result of any cause, reported as the count of participants still alive without recurrence at the end of study follow-up.
Time frame: An average of 2.6 years (full range 2.1 to 3.1 years)
Population: 14 of 32 participants were enrolled in the Phase II portion of the study. Of these 14, one participant withdrew prior to surgery and was therefore not evaluable for this outcome
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Escalation Phase Ib | Disease-free Survival (DFS) Rate | 10 Participants |
Secondary
Disease-free Survival (DFS) Rate Based on Pathological Complete Response (pCR).
Phase II only - a comparison of DFS for patients who achieve pCR and those who do not. DFS will be defined as the time from surgical resection until disease recurrence or death as a result of any cause, reported as the count of participants still alive without recurrence at the end of study follow-up.
Time frame: an average of 2.6 years (full range 2.1 to 3.1 years)
Population: 14 of 32 participants were enrolled in the Phase II portion of the study. Of these 14, one participant withdrew prior to surgery and was therefore not evaluable for this outcome
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Escalation Phase Ib | Disease-free Survival (DFS) Rate Based on Pathological Complete Response (pCR). | pathological complete response (pCR) | 2 Participants |
| Dose Escalation Phase Ib | Disease-free Survival (DFS) Rate Based on Pathological Complete Response (pCR). | Did not achieve pCR | 8 Participants |
Secondary
Number of Participants With Grade 3 or Higher, Treatment-related Toxicities
Toxicity profile of CRLX101 when combined with capecitabine + radiotherapy to treat patients with locally advanced rectal cancer. Phase Ib and Phase II - Safety is the reported adverse event (AE) profile characterized by NCI CTCAE v4.0. The profile was limited to grade 3 or higher, treatment related AEs.
Time frame: 12 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dose Escalation Phase Ib | Number of Participants With Grade 3 or Higher, Treatment-related Toxicities | Colitis | 1 participants with AE |
| Dose Escalation Phase Ib | Number of Participants With Grade 3 or Higher, Treatment-related Toxicities | Dermatitis, radiation | 1 participants with AE |
| Dose Escalation Phase Ib | Number of Participants With Grade 3 or Higher, Treatment-related Toxicities | Diarrhea | 1 participants with AE |
| Dose Escalation Phase Ib | Number of Participants With Grade 3 or Higher, Treatment-related Toxicities | Hypophosphatemia | 1 participants with AE |
| Dose Escalation Phase Ib | Number of Participants With Grade 3 or Higher, Treatment-related Toxicities | Lymphocyte count decreased | 9 participants with AE |
| Dose Escalation Phase Ib | Number of Participants With Grade 3 or Higher, Treatment-related Toxicities | Rectal obstruction | 1 participants with AE |
| Dose Escalation Phase Ib | Number of Participants With Grade 3 or Higher, Treatment-related Toxicities | White blood cell decreased | 1 participants with AE |
Secondary
Overall Survival (OS) Based on Pathological Complete Response (pCR).
Phase II only - a comparison of OS for patients who achieve pCR and those who do not. OS is defined as the time from surgical resection until death reported as the count of participants still alive at the end of study follow-up.
Time frame: an average of 2.6 years (full range 2.1 to 3.1 years)
Population: 14 of 32 participants were enrolled in the Phase II portion of the study. Of these 14, one participant withdrew prior to surgery and was therefore not evaluable for this outcome
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Escalation Phase Ib | Overall Survival (OS) Based on Pathological Complete Response (pCR). | pathological complete response (pCR) | 2 Participants |
| Dose Escalation Phase Ib | Overall Survival (OS) Based on Pathological Complete Response (pCR). | Did not achieve pCR | 11 Participants |
Secondary
Overall Survival (OS) Rate
Phase II only - OS is defined as the time from surgical resection until death reported as the count of participants still alive at the end of study follow-up.
Time frame: an average of 2.6 years (full range 2.1 to 3.1 years)
Population: 14 of 32 participants were enrolled in the Phase II portion of the study. Of these 14, one participant withdrew prior to surgery and was therefore not evaluable for this outcome
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Escalation Phase Ib | Overall Survival (OS) Rate | 13 Participants |
Secondary
Pathological Response Rate
Pathologic response will be made based on microscopic assessment of the surgical specimen at the primary treatment site, including regional nodes and any peritumoral satellite nodules in the specimen, and categorized as outlined below as per the American Joint Committee on Cancer (AJCC) Cancer Staging Manual 7th edition.Determination of pathological response will be reported by the local pathologist. * Pathologic Complete Response (pCR): No gross or microscopic tumor identified anywhere within the surgical specimen. This must include: No evidence of malignant cells in the primary tumor specimen and No lymph nodes that contain tumor. * Moderate response: Single cells or small groups of cancer cells * Minimal response: Residual cancer outgrown by fibrosis * Poor response:Minimal or no tumor kill; extensive residual cancer
Time frame: 12 weeks
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Escalation Phase Ib | Pathological Response Rate | pCR | 6 Participants |
| Dose Escalation Phase Ib | Pathological Response Rate | Moderate response | 18 Participants |
| Dose Escalation Phase Ib | Pathological Response Rate | Minimal response | 7 Participants |
| Dose Escalation Phase Ib | Pathological Response Rate | Unknown | 1 Participants |