Neoadjuvant Chemoradiotherapy With CRLX-101 and Capecitabine for Rectal Cancer

• Sponsor: UNC Lineberger Comprehensive Cancer Center (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02010567
• Collaborator: Cerulean Pharma Inc. (Industry)
• Enrollment: 32
• Locations: 6
• Arms: 2
• Duration (Months): 66.8
• Patients Per Site: 5.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Rectal Cancer	Drug: CRLX101; Drug: Capecitabine; Radiation: Radiotherapy; Procedure: Surgery	Phase 1/Phase 2

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).

Study Design

• Study Type: Interventional
• Actual Enrollment: 32 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase Ib/II Study of Neoadjuvant Chemoradiotherapy With CRLX-101 and Capecitabine for Locally Advanced Rectal Cancer
• Study Start Date: Dec 1, 2013
• Actual Primary Completion Date: Sep 16, 2016
• Actual Study Completion Date: Jun 25, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CLRX101 MTD/RP2D 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.	Drug: CRLX101; CRLX101 is an experimental nanoparticle formulation of the anticancer agent camptothecin manufactured by Cerulean Pharma Inc..; Drug: Capecitabine; 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.; Other Names: Xeloda ; Radiation: Radiotherapy; 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.; Other Names: Intensity Modulated Radiation Therapy IMRT
Experimental: Chemoradiotherapy + Surgery 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.	Drug: CRLX101; CRLX101 is an experimental nanoparticle formulation of the anticancer agent camptothecin manufactured by Cerulean Pharma Inc..; Drug: Capecitabine; 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.; Other Names: Xeloda ; Radiation: Radiotherapy; 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.; Other Names: Intensity Modulated Radiation Therapy IMRT ; Procedure: Surgery; 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.; Other Names: Resection Surgical resection

Outcome Measures

Primary Outcome Measures

1. 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

2. 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 Outcome Measures

1. 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

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

1. Age ≥18 years old

2. Women of childbearing potential (WOCBP) must have negative pregnancy test within 7 days prior to D1 of treatment

3. Recommendation to undergo concurrent chemoradiation, as determined by the treating physician

4. Ability to swallow oral medications

5. 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

6. Informed consent reviewed and signed

Exclusion Criteria:

Patients meeting any of the following exclusion criteria will not be able to participate in this study:

1. Grade 2 or higher diarrhea at baseline unless deemed by the investigator to be caused by laxatives prescribed for symptomatic partial obstruction (e.g. MiraLAX®)

2. Not deemed a candidate for concurrent chemoradiation for medical reasons, such as uncontrolled infection (including HIV), uncontrolled diabetes mellitus or cardiac disease which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient.

3. Specific laboratory exclusion values, including:

• Hemoglobin < 10.0 g/dL for males and ≤ 9.0 g/dL for females (transfusion allowed to achieve or maintain levels)

• Absolute neutrophil count (ANC) < 1,500/mm3

• Platelet count < 100,000/mm3

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) > 2.5 times upper level of normal (ULN)

• Alkaline phosphatase > 2.5 times ULN

• Total bilirubin > 1.5 times ULN

• Creatinine clearance < 50 mL/min

• International normalized ratio (INR) >2

1. Known dihydropyrimidine dehydrogenase (DPD) deficiency

2. History of Gilbert's syndrome

3. Those who require therapeutic anticoagulation with coumarin-derivative anticoagulants

4. Unable to provide informed consent

5. Receiving any other concurrent cytotoxic, biologic agent(s) or investigational agent

6. Patients with a "currently active" second malignancy other than non-melanoma skin cancers, non-invasive bladder cancer, "low risk" adenocarcinoma of the prostate and carcinoma in situ of the cervix. Patients are not considered to have a "currently active" malignancy if they have completed therapy and are free of disease for ≥ 2 years.

7. Previous pelvic radiation therapy

8. Prior treatment with a topoisomerase I inhibitor (i.e. irinotecan, topotecan)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Rocky Mountain Cancer Center	Denver	Colorado	United States	80218
2	Indiana University Simon Cancer Center	Indianapolis	Indiana	United States	46202
3	University of North Carolina	Chapel Hill	North Carolina	United States	27599
4	Rex Cancer Center at Rex Hospital	Raleigh	North Carolina	United States	27607
5	Wake Forest University Comprehensive Cancer Center	Winston-Salem	North Carolina	United States	27157
6	Swedish Cancer Institute	Seattle	Washington	United States	98104

Sponsors and Collaborators

• UNC Lineberger Comprehensive Cancer Center
• Cerulean Pharma Inc.

Investigators

• Principal Investigator: Andrew Wang, MD, UNC Lineberger Comprehensive Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Lineberger Comprehensive Cancer Center website

Publications

None provided.

• Responsible Party: UNC Lineberger Comprehensive Cancer Center
• ClinicalTrials.gov Identifier: NCT02010567
• Other Study ID Numbers: LCCC 1315
• First Posted: Dec 12, 2013
• Last Update Posted: Nov 3, 2020
• Last Verified: Oct 1, 2020

• Keywords provided by UNC Lineberger Comprehensive Cancer Center: rectal cancer; colorectal cancer; locally advanced rectal cancer; locally advanced rectal cancer (resectable); locally advanced rectal cancer (non-resectable); chemoradiotherapy; nanopharmaceutical; CLRX101; camptothecin; capecitabine
• Additional relevant MeSH terms: Rectal Neoplasms; Capecitabine

Study Results

Participant Flow

Recruitment Details	Patients were recruited from 5 medical institutions between December 2013 and September 2016
Pre-assignment Detail	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.

Arm/Group Title	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
Arm/Group Description	CRLX101 12mg/ 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	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	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	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	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
Period Title: Overall Study
STARTED	3	6	14	3	6
COMPLETED	3	6	13	3	5
NOT COMPLETED	0	0	1	0	1

Baseline Characteristics

Arm/Group Title	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
Arm/Group Description	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	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	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	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	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	Total of all reporting groups
Overall Participants	3	6	14	3	6	32
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	2 66.7%	4 66.7%	14 100%	3 100%	5 83.3%	28 87.5%
>=65 years	1 33.3%	2 33.3%	0 0%	0 0%	1 16.7%	4 12.5%
Sex: Female, Male (Count of Participants)
Female	2 66.7%	1 16.7%	4 28.6%	0 0%	3 50%	10 31.3%
Male	1 33.3%	5 83.3%	10 71.4%	3 100%	3 50%	22 68.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	1 16.7%	3 21.4%	0 0%	1 16.7%	5 15.6%
White	3 100%	5 83.3%	11 78.6%	3 100%	4 66.7%	26 81.3%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	1 16.7%	1 3.1%
Region of Enrollment (Count of Participants)
United States	3 100%	6 100%	14 100%	3 100%	6 100%	32 100%

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose (MTD) of CRLX101 When Added to Standard Neoadjuvant Chemoradiotherapy Consisting of Capecitabine + Radiotherapy in Locally Advanced Rectal Cancer
Description	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

Outcome Measure Data

Analysis Population Description

Since this objective applies only to Phase Ib patients, the Phase II cohort patients were not included

Arm/Group Title	Dose Escalation Phase Ib
Arm/Group Description	Phase Ib patients who received at least one dose of CRLX101 at either 12mg/m2 or 15mg/m2 either every other week (Cohort A) or weekly (Cohort B)
Measure Participants	18
Number [mg/m^2 every other week]	15

2. Primary Outcome

Title	Pathological Complete Response (pCR) Rate
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Participants
Arm/Group Description	All resectable participants who received CRLX101 + capecitabine (Cape) and radiation therapy (XRT) regardless of dose and timing of treatment
Measure Participants	32
Number (95% Confidence Interval) [percentage of participants with pCR]	19 633.3%

3. Secondary Outcome

Title	Pathological Response Rate
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Participants
Arm/Group Description	All resectable participants who received CRLX101 + capecitabine (Cape) and radiation therapy (XRT) regardless of dose and timing of treatment
Measure Participants	32
pCR	6 200%
Moderate response	18 600%
Minimal response	7 233.3%
Unknown	1 33.3%

4. Secondary Outcome

Title	Number of Participants With Grade 3 or Higher, Treatment-related Toxicities
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Participants
Arm/Group Description	All resectable participants who received CRLX101 + capecitabine (Cape) and radiation therapy (XRT) regardless of dose and timing of treatment
Measure Participants	32
Colitis	1 33.3%
Dermatitis, radiation	1 33.3%
Diarrhea	1 33.3%
Hypophosphatemia	1 33.3%
Lymphocyte count decreased	9 300%
Rectal obstruction	1 33.3%
White blood cell decreased	1 33.3%

5. Secondary Outcome

Title	Disease-free Survival (DFS) Rate
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Cohort A, Phase II, Dose Level 2
Arm/Group Description	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
Measure Participants	13
Count of Participants [Participants]	10 333.3%

6. Secondary Outcome

Title	Overall Survival (OS) Rate
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Cohort A, Phase II, Dose Level 2
Arm/Group Description	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
Measure Participants	13
Count of Participants [Participants]	13 433.3%

7. Secondary Outcome

Title	Disease-free Survival (DFS) Rate Based on Pathological Complete Response (pCR).
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Cohort A, Phase II, Dose Level 2
Arm/Group Description	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
Measure Participants	13
pathological complete response (pCR)	2 66.7%
Did not achieve pCR	8 266.7%

8. Secondary Outcome

Title	Overall Survival (OS) Based on Pathological Complete Response (pCR).
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Cohort A, Phase II, Dose Level 2
Arm/Group Description	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
Measure Participants	13
pathological complete response (pCR)	2 66.7%
Did not achieve pCR	11 366.7%

Adverse Events

Time Frame	Adverse events were collected up to 30 days after treatment was discontinued (approximately 12 weeks from study entry)
Adverse Event Reporting Description	All patients were evaluated for serious adverse events (SAEs)
Arm/Group Title	Cohort A, Phase Ib, Level 1		Cohort A, Phase Ib, Level 2		Cohort A, Phase II, Level 2		Cohort B, Phase Ib, Level 1		Cohort B, Phase Ib, Level 2
Arm/Group Description	12mg/m^2 CRLX101 every other week + 825mg/m^2 BID Capecitabine + XRT		15mg/m^2 CRLX101 every other week + 825mg/m^2 BID Capecitabine + XRT		15mg/m^2 CRLX101 IV weekly + 825mg/m^2 BID Capecitabine + XRT		12mg/m^2 CRLX101 IV weekly + 825mg/m^2 BID Capecitabine + XRT		15mg/m^2 CRLX101 IV weekly + 825mg/m^2 BID Capecitabine + XRT
All Cause Mortality
	Cohort A, Phase Ib, Level 1		Cohort A, Phase Ib, Level 2		Cohort A, Phase II, Level 2		Cohort B, Phase Ib, Level 1		Cohort B, Phase Ib, Level 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/6 (0%)		0/14 (0%)		0/3 (0%)		0/6 (0%)
Serious Adverse Events
	Cohort A, Phase Ib, Level 1		Cohort A, Phase Ib, Level 2		Cohort A, Phase II, Level 2		Cohort B, Phase Ib, Level 1		Cohort B, Phase Ib, Level 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/6 (0%)		1/14 (7.1%)		0/3 (0%)		0/6 (0%)
Gastrointestinal disorders
Colonic obstruction	0/3 (0%)	0	0/6 (0%)	0	1/14 (7.1%)	1	0/3 (0%)	0	0/6 (0%)	0
Other (Not Including Serious) Adverse Events
	Cohort A, Phase Ib, Level 1		Cohort A, Phase Ib, Level 2		Cohort A, Phase II, Level 2		Cohort B, Phase Ib, Level 1		Cohort B, Phase Ib, Level 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		6/6 (100%)		14/14 (100%)		3/3 (100%)		6/6 (100%)
Blood and lymphatic system disorders
Anemia	1/3 (33.3%)	1	4/6 (66.7%)	4	11/14 (78.6%)	11	2/3 (66.7%)	2	4/6 (66.7%)	4
Thrombotic thrombocytopenic purpura	0/3 (0%)	0	2/6 (33.3%)	2	0/14 (0%)	0	0/3 (0%)	0	0/6 (0%)	0
Cardiac disorders
Atrial fibrillation	0/3 (0%)	0	1/6 (16.7%)	1	0/14 (0%)	0	0/3 (0%)	0	0/6 (0%)	0
Ventricular arrhythmia	0/3 (0%)	0	0/6 (0%)	0	0/14 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1
Ear and labyrinth disorders
Ear pain	0/3 (0%)	0	0/6 (0%)	0	1/14 (7.1%)	1	0/3 (0%)	0	0/6 (0%)	0
Hearing impaired	0/3 (0%)	0	1/6 (16.7%)	1	0/14 (0%)	0	0/3 (0%)	0	0/6 (0%)	0
Gastrointestinal disorders
Abdominal pain	0/3 (0%)	0	4/6 (66.7%)	4	2/14 (14.3%)	2	0/3 (0%)	0	3/6 (50%)	3
Anal hemorrhage	0/3 (0%)	0	0/6 (0%)	0	0/14 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1
Anal pain	0/3 (0%)	0	0/6 (0%)	0	1/14 (7.1%)	1	0/3 (0%)	0	0/6 (0%)	0
Bloating	0/3 (0%)	0	0/6 (0%)	0	1/14 (7.1%)	1	0/3 (0%)	0	0/6 (0%)	0
Colitis	0/3 (0%)	0	0/6 (0%)	0	1/14 (7.1%)	1	0/3 (0%)	0	0/6 (0%)	0
Constipation	1/3 (33.3%)	1	4/6 (66.7%)	4	4/14 (28.6%)	4	3/3 (100%)	3	1/6 (16.7%)	1
Diarrhea	2/3 (66.7%)	2	4/6 (66.7%)	4	10/14 (71.4%)	10	0/3 (0%)	0	5/6 (83.3%)	5
Flatulence	0/3 (0%)	0	0/6 (0%)	0	1/14 (7.1%)	1	0/3 (0%)	0	0/6 (0%)	0
Gastroesophageal reflux disease	0/3 (0%)	0	0/6 (0%)	0	1/14 (7.1%)	1	1/3 (33.3%)	1	0/6 (0%)	0
Hemorrhoids	1/3 (33.3%)	1	1/6 (16.7%)	1	1/14 (7.1%)	1	0/3 (0%)	0	0/6 (0%)	0
Ileus	0/3 (0%)	0	0/6 (0%)	0	1/14 (7.1%)	1	0/3 (0%)	0	0/6 (0%)	0
Mucositis oral	0/3 (0%)	0	0/6 (0%)	0	1/14 (7.1%)	1	0/3 (0%)	0	0/6 (0%)	0
Nausea	3/3 (100%)	3	3/6 (50%)	3	5/14 (35.7%)	5	1/3 (33.3%)	1	2/6 (33.3%)	2
Rectal hemorrhage	1/3 (33.3%)	1	2/6 (33.3%)	2	5/14 (35.7%)	5	1/3 (33.3%)	1	1/6 (16.7%)	1
Rectal mucositis	0/3 (0%)	0	1/6 (16.7%)	1	0/14 (0%)	0	0/3 (0%)	0	0/6 (0%)	0
Rectal obstruction	1/3 (33.3%)	1	0/6 (0%)	0	0/14 (0%)	0	0/3 (0%)	0	0/6 (0%)	0
Rectal pain	3/3 (100%)	3	3/6 (50%)	3	4/14 (28.6%)	4	3/3 (100%)	3	3/6 (50%)	3
Vomiting	0/3 (0%)	0	1/6 (16.7%)	1	1/14 (7.1%)	1	1/3 (33.3%)	1	1/6 (16.7%)	1
General disorders
Chills	0/3 (0%)	0	0/6 (0%)	0	0/14 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0
Edema limbs	0/3 (0%)	0	0/6 (0%)	0	0/14 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1
Fatigue	2/3 (66.7%)	2	3/6 (50%)	3	11/14 (78.6%)	11	2/3 (66.7%)	2	5/6 (83.3%)	5
Fever	0/3 (0%)	0	0/6 (0%)	0	1/14 (7.1%)	1	1/3 (33.3%)	1	0/6 (0%)	0
Infusion related reaction	0/3 (0%)	0	0/6 (0%)	0	1/14 (7.1%)	1	0/3 (0%)	0	0/6 (0%)	0
Non-cardiac chest pain	0/3 (0%)	0	1/6 (16.7%)	1	0/14 (0%)	0	0/3 (0%)	0	0/6 (0%)	0
Pain	0/3 (0%)	0	0/6 (0%)	0	2/14 (14.3%)	2	0/3 (0%)	0	0/6 (0%)	0
Infections and infestations
Upper respiratory infection	0/3 (0%)	0	0/6 (0%)	0	1/14 (7.1%)	1	0/3 (0%)	0	0/6 (0%)	0
Vaginal infection	0/3 (0%)	0	0/6 (0%)	0	1/14 (7.1%)	1	0/3 (0%)	0	1/6 (16.7%)	1
Injury, poisoning and procedural complications
Dermatitis radiation	0/3 (0%)	0	1/6 (16.7%)	1	0/14 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1
Investigations
Alanine aminotransferase increased	0/3 (0%)	0	1/6 (16.7%)	1	1/14 (7.1%)	1	1/3 (33.3%)	1	1/6 (16.7%)	1
Alkaline phosphatase increased	0/3 (0%)	0	1/6 (16.7%)	1	0/14 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1
Aspartate aminotransferase increased	0/3 (0%)	0	1/6 (16.7%)	1	1/14 (7.1%)	1	0/3 (0%)	0	1/6 (16.7%)	1
Blood bilirubin increased	0/3 (0%)	0	1/6 (16.7%)	1	1/14 (7.1%)	1	0/3 (0%)	0	0/6 (0%)	0
Cholesterol high	0/3 (0%)	0	1/6 (16.7%)	1	0/14 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0
Creatinine increased	0/3 (0%)	0	0/6 (0%)	0	1/14 (7.1%)	1	0/3 (0%)	0	0/6 (0%)	0
Lymphocyte count decreased	3/3 (100%)	3	3/6 (50%)	3	8/14 (57.1%)	8	2/3 (66.7%)	2	4/6 (66.7%)	4
Neutrophil count decreased	2/3 (66.7%)	2	0/6 (0%)	0	2/14 (14.3%)	2	2/3 (66.7%)	2	3/6 (50%)	3
Platelet count decreased	0/3 (0%)	0	3/6 (50%)	3	3/14 (21.4%)	3	0/3 (0%)	0	0/6 (0%)	0
Weight loss	0/3 (0%)	0	0/6 (0%)	0	1/14 (7.1%)	1	0/3 (0%)	0	1/6 (16.7%)	1
White blood cell decreased	3/3 (100%)	3	2/6 (33.3%)	2	5/14 (35.7%)	5	2/3 (66.7%)	2	3/6 (50%)	3
Metabolism and nutrition disorders
Anorexia	1/3 (33.3%)	1	1/6 (16.7%)	1	4/14 (28.6%)	4	1/3 (33.3%)	1	2/6 (33.3%)	2
Dehydration	0/3 (0%)	0	0/6 (0%)	0	0/14 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1
Hyperglycemia	0/3 (0%)	0	4/6 (66.7%)	4	5/14 (35.7%)	5	0/3 (0%)	0	1/6 (16.7%)	1
Hyperkalemia	0/3 (0%)	0	2/6 (33.3%)	2	1/14 (7.1%)	1	0/3 (0%)	0	2/6 (33.3%)	2
Hypermagnesemia	0/3 (0%)	0	1/6 (16.7%)	1	5/14 (35.7%)	5	0/3 (0%)	0	2/6 (33.3%)	2
Hypertriglyceridemia	0/3 (0%)	0	1/6 (16.7%)	1	0/14 (0%)	0	0/3 (0%)	0	0/6 (0%)	0
Hypoalbuminemia	0/3 (0%)	0	2/6 (33.3%)	2	3/14 (21.4%)	3	2/3 (66.7%)	2	0/6 (0%)	0
Hypocalcemia	0/3 (0%)	0	0/6 (0%)	0	3/14 (21.4%)	3	3/3 (100%)	3	0/6 (0%)	0
Hypoglycemia	0/3 (0%)	0	1/6 (16.7%)	1	0/14 (0%)	0	0/3 (0%)	0	0/6 (0%)	0
Hypokalemia	0/3 (0%)	0	1/6 (16.7%)	1	1/14 (7.1%)	1	1/3 (33.3%)	1	0/6 (0%)	0
Hypomagnesemia	0/3 (0%)	0	0/6 (0%)	0	2/14 (14.3%)	2	0/3 (0%)	0	0/6 (0%)	0
Hyponatremia	0/3 (0%)	0	1/6 (16.7%)	1	2/14 (14.3%)	2	2/3 (66.7%)	2	4/6 (66.7%)	4
Hypophosphatemia	0/3 (0%)	0	1/6 (16.7%)	1	4/14 (28.6%)	4	3/3 (100%)	3	3/6 (50%)	3
Musculoskeletal and connective tissue disorders
Back pain	0/3 (0%)	0	0/6 (0%)	0	3/14 (21.4%)	3	0/3 (0%)	0	0/6 (0%)	0
Generalized muscle weakness	0/3 (0%)	0	0/6 (0%)	0	1/14 (7.1%)	1	0/3 (0%)	0	0/6 (0%)	0
Muscle weakness lower limb	0/3 (0%)	0	0/6 (0%)	0	0/14 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1
Pain in extremity	0/3 (0%)	0	1/6 (16.7%)	1	1/14 (7.1%)	1	0/3 (0%)	0	0/6 (0%)	0
Nervous system disorders
Dizziness	0/3 (0%)	0	0/6 (0%)	0	1/14 (7.1%)	1	1/3 (33.3%)	1	0/6 (0%)	0
Headache	0/3 (0%)	0	1/6 (16.7%)	1	0/14 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1
Memory impairment	0/3 (0%)	0	1/6 (16.7%)	1	0/14 (0%)	0	0/3 (0%)	0	0/6 (0%)	0
Peripheral sensory neuropathy	0/3 (0%)	0	0/6 (0%)	0	1/14 (7.1%)	1	0/3 (0%)	0	0/6 (0%)	0
Somnolence	0/3 (0%)	0	1/6 (16.7%)	1	0/14 (0%)	0	0/3 (0%)	0	0/6 (0%)	0
Psychiatric disorders
Anxiety	0/3 (0%)	0	2/6 (33.3%)	2	2/14 (14.3%)	2	1/3 (33.3%)	1	0/6 (0%)	0
Depression	0/3 (0%)	0	0/6 (0%)	0	0/14 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0
Insomnia	1/3 (33.3%)	1	1/6 (16.7%)	1	0/14 (0%)	0	0/3 (0%)	0	0/6 (0%)	0
Renal and urinary disorders
Bladder spasm	0/3 (0%)	0	0/6 (0%)	0	0/14 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0
Cystitis noninfective	0/3 (0%)	0	2/6 (33.3%)	2	4/14 (28.6%)	4	1/3 (33.3%)	1	2/6 (33.3%)	2
Hematuria	0/3 (0%)	0	0/6 (0%)	0	1/14 (7.1%)	1	0/3 (0%)	0	2/6 (33.3%)	2
Proteinuria	0/3 (0%)	0	0/6 (0%)	0	0/14 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1
Renal and urinary disorders - Other, specify	0/3 (0%)	0	0/6 (0%)	0	1/14 (7.1%)	1	0/3 (0%)	0	0/6 (0%)	0
Urinary frequency	1/3 (33.3%)	1	2/6 (33.3%)	2	5/14 (35.7%)	5	2/3 (66.7%)	2	2/6 (33.3%)	2
Urinary tract pain	3/3 (100%)	3	1/6 (16.7%)	1	1/14 (7.1%)	1	1/3 (33.3%)	1	0/6 (0%)	0
Urinary urgency	1/3 (33.3%)	1	1/6 (16.7%)	1	2/14 (14.3%)	2	1/3 (33.3%)	1	1/6 (16.7%)	1
Reproductive system and breast disorders
Perineal pain	0/3 (0%)	0	0/6 (0%)	0	0/14 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1
Vaginal pain	0/3 (0%)	0	0/6 (0%)	0	0/14 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1
Respiratory, thoracic and mediastinal disorders
Hiccups	0/3 (0%)	0	0/6 (0%)	0	0/14 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1
Nasal congestion	0/3 (0%)	0	0/6 (0%)	0	1/14 (7.1%)	1	0/3 (0%)	0	0/6 (0%)	0
Productive cough	0/3 (0%)	0	1/6 (16.7%)	1	0/14 (0%)	0	0/3 (0%)	0	0/6 (0%)	0
Sleep apnea	0/3 (0%)	0	0/6 (0%)	0	1/14 (7.1%)	1	0/3 (0%)	0	0/6 (0%)	0
Sore throat	0/3 (0%)	0	0/6 (0%)	0	0/14 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1
Skin and subcutaneous tissue disorders
Dry skin	0/3 (0%)	0	0/6 (0%)	0	1/14 (7.1%)	1	0/3 (0%)	0	2/6 (33.3%)	2
Pain of skin	0/3 (0%)	0	0/6 (0%)	0	0/14 (0%)	0	0/3 (0%)	0	2/6 (33.3%)	2
Palmar-plantar erythrodysesthesia syndrome	1/3 (33.3%)	1	1/6 (16.7%)	1	0/14 (0%)	0	0/3 (0%)	0	0/6 (0%)	0
Rash acneiform	0/3 (0%)	0	0/6 (0%)	0	0/14 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0
Rash maculo-papular	0/3 (0%)	0	0/6 (0%)	0	0/14 (0%)	0	1/3 (33.3%)	1	1/6 (16.7%)	1
Skin and subcutaneous tissue disorders - Other, specify	0/3 (0%)	0	0/6 (0%)	0	1/14 (7.1%)	1	0/3 (0%)	0	0/6 (0%)	0
Skin and subcutaneous tissue disorders - Other, specify	0/3 (0%)	0	0/6 (0%)	0	0/14 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0
Skin hyperpigmentation	0/3 (0%)	0	0/6 (0%)	0	1/14 (7.1%)	1	0/3 (0%)	0	0/6 (0%)	0
Vascular disorders
Hypertension	0/3 (0%)	0	3/6 (50%)	3	4/14 (28.6%)	4	1/3 (33.3%)	1	1/6 (16.7%)	1
Phlebitis	0/3 (0%)	0	0/6 (0%)	0	1/14 (7.1%)	1	0/3 (0%)	0	0/6 (0%)	0
Thromboembolic event	0/3 (0%)	0	0/6 (0%)	0	1/14 (7.1%)	1	0/3 (0%)	0	0/6 (0%)	0

Limitations/Caveats

Follow-up of participants was ended early, resulting in few or no observed events (progression or death) for all survival endpoints.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.