TAS-OX for Refractory Metastatic Colon Cancer

• Sponsor: Yale University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02848079
• Collaborator: (none)
• Enrollment: 41
• Location: 1
• Arm: 1
• Actual Duration (Months): 43
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

This study will examine the safety and effectiveness of oxaliplatin in combination with TAS-102 (TAS-OX) for treatment of patients with metastatic colorectal cancer whose cancer has progressed or recurred after FOLFOX chemotherapy.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Neoplasms	Drug: combined TAS-102 and TAS-OX	Phase 1/Phase 2

Detailed Description

TAS-102 is an oral agent, which consists of a combination of a novel antimetabolite 5-trifluorothymidine (FTD) and a thymidine phosphorylase inhibitor (TPI) that prevents degradation of FTD. It has demonstrated activity in chemorefractory metastatic colorectal cancer (mCRC) patients. In the Japanese randomized phase II trial, TAS-102 improved medial overall survival when compared to placebo (9.0 vs.6.6 months, Hazard Ratio (HR) 0.56) in patients with mCRC refractory to 5-fluorouracil (5-FU), irinotecan and oxaliplatin. Subsequently, a randomized phase III study conducted in 13 countries (RECOURSE trial) confirmed this benefit on overall survival when compared to placebo (7.1 months vs. 5.3 months, HR 0.68) in patients with refractory metastatic colorectal cancer (CRC) 5.

Oxaliplatin is a third generation platinum compound, which is active when used together with 5-FU in the treatment of mCRC (FOLFOX). FOLFOX chemotherapy, which is frequently combined with anti-angiogenic agent Bevacizumab, is widely accepted as the preferred first-line regimen in the treatment of this disease in the US. Oxaliplatin is also frequently reintroduced in more advanced settings. Reintroduction is seen after progression on maintenance therapy, after resolution of previous treatment limiting neuropathy, after disease recurrence post adjuvant treatment or post metastasectomy. In the control arm of a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer (OPTIMOX1 study), oxaliplatin was reintroduced in 27% of patients. Although patients derive clinical benefit when oxaliplatin is reintroduced, the response rates are not as robust as during initial exposures. Decreased efficacy may be at least in part due to prolonged exposure and resultant resistance to 5-FU, which is a backbone in maintenance and in oxaliplatin containing regimens. Hence, the investigators propose exploring the safety and efficacy of oxaliplatin in combination with an alternative anti-metabolite TAS-102 (TAS-OX).

TAS-102 has demonstrated activity in 5-FU refractory mCRC, so the investigators hypothesize that TAS-OX may serve as an alternative drug combination for patients who have progressed or recurred after FOLFOX, and who are candidates for additional oxaliplatin therapy.

This is a 2-part clinical trial with TAS-102 in combination with oxaliplatin. The first part will be a dose-finding run-in phase and will enroll 3-18 patients. The second part, the focus of this study, will be a single arm cohort , which will further evaluate the safety, as well as efficacy, of TAS-OX in the treatment of mCRC. The subjects in part 2 will be treated with the drug doses determined in Part 1 of the trial. Up to 50 patients will be enrolled in part 2. Anticipated enrollment may be as high as 68 patients. Maximum potential enrollment is listed under anticipated enrollment, below.

Study Design

• Study Type: Interventional
• Actual Enrollment: 41 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: TAS-102 and Oxaliplatin (TAS-OX) for Refractory Metastatic Colon Cancer
• Actual Study Start Date: Oct 31, 2016
• Actual Primary Completion Date: Jun 2, 2020
• Actual Study Completion Date: Jun 2, 2020

Arms and Interventions

Arm

Intervention/Treatment

Experimental: combined TAS-102 and oxaliplatin Combination treatment with TAS-102 and oxaliplatin. Combination treatment with TAS-102 and oxaliplatin. TAS-102 is an oral medication; oxaliplatin (TAS-OX) is given by infusion. In Part 1 treatments were started at level 1 doses, which were based on prior clinical experience with the medications studied. Dose escalation followed a traditional "3+3" design. The subjects in Part 2 were treated with dose level 3. Oxaliplatin infusion was given on day 1 of each cycle. TAS-102 was taken twice daily on days 1-5 of each cycle.

Drug: combined TAS-102 and TAS-OX; Combination treatment with TAS-102 and oxaliplatin. TAS-102 is an oral medication; oxaliplatin (TAS-OX) is given by infusion.

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate [up to 30 days following discontinuation of treatment]

   Overall Response Rate was measured by Response Evaluation Criteria In Solid Tumor (RECIST) 1.1 criteria. Tumors were assessed with CT or MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.".

Secondary Outcome Measures

1. Progression Free Survival [from the date of start of treatment to the date of first documented progression or any cause of death assessed up to 12 months.]

   Progression Free Survival was assessed according to RECIST criteria version 1.1. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

2. Overall Survival [from the date of start of treatment to the date of any cause of death assessed up to 24 months.]

   Overall Survival was assessed by the time to death from start of study.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Histologically confirmed stage IV colon cancer (AJCC 7th edition) that has progressed after standard therapy that included 5-FU, irinotecan and oxaliplatin. Patients who could not tolerate standard agents because of unacceptable, but reversible, toxicity necessitating their discontinuation will be allowed to participate.

2. Patients who had received adjuvant chemotherapy and had recurrence during or within 6 months of completion of the adjuvant chemotherapy will be allowed to count the adjuvant therapy as one chemotherapy regimen.

3. Progression of disease must be documented on the most recent scan.

4. Presence of measurable disease (not required for Phase 1 portion of the trial).

5. Retrovirus-associated DNA sequences (RAS) mutation and mismatch repair (MMR) status must be determined (or tissue availability for testing if not already determined)

6. Age 18 years or older.

7. Eastern Cooperative Oncology Group (ECOG) performance status 0-1.

8. Life expectancy of at least 3 months.

9. Patient with adequate organ function:

10. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

11. Hemoglobin ≥ 9 g/dL

12. Platelets (PLT) ≥ 75 x 109/L

13. Aspartate aminotransferase (AST)/Alanine aminotransferase (ALT) ≤ 5 x Upper limit of normal (ULN)

14. Total serum bilirubin of ≤1.5 mg/dL (except for Grade 1 hyperbilirubinemia due solely to a medical diagnosis of Gilbert's syndrome).

15. Albumin ≥ 2.5 g/dL

16. Serum creatinine ≤ 1.5 x institutional ULN (Cockcroft and Gault formula)

17. Adequate contraception if applicable.

18. Women who are nursing must discontinue nursing prior to enrollment in the program.

19. Ability to take oral medication (i.e. no feeding tube).

20. Patient able and willing to comply with study procedures as per protocol.

21. Patient able to understand and willing to sign and date the written voluntary informed consent form (ICF) at screening visit prior to any protocol-specific procedures.

Exclusion Criteria:

1. Patients who have previously received TAS-102.

2. Grade 2 or higher peripheral neuropathy.

3. Symptomatic Central nervous system (CNS) metastases requiring treatment.

4. Other active malignancy within the last 3 years (except for non-melanoma skin cancer or a non-invasive/in situ cancer).

5. Pregnancy or breast feeding.

6. Current therapy with other investigational agents.

7. Active infection with body temperature ≥38°C due to infection.

8. Major surgery within prior 4 weeks (the surgical incision should be fully healed prior to drug administration).

9. Any anticancer therapy within prior 3 weeks of first dose of study drug.

10. History of allergic reactions attributed to compounds of similar chemical or biologic composition to TAS-102.

11. Current therapy with other investigational agents or participation in another clinical study or any investigational agent received within prior 4 weeks.

12. Grade 3 or higher hypersensitivity reaction to oxaliplatin, or grade 1-2 hypersensitivity reaction to oxaliplatin not controlled with pre-medication.

13. Unresolved toxicity of greater than or equal to Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 attributed to any prior therapies (excluding anemia, alopecia, skin pigmentation, and platinum-induced neurotoxicity).

14. Extended field radiation within prior 4 weeks of first dose of study drug or limited field radiation within prior 2 weeks of first dose of study drug.

15. Psychological, familial, or sociological condition potentially hampering compliance with the study protocol and follow-up schedule.

16. Involvement in the planning and/or conduct of the study.

17. Previous enrollment in the present study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Yale Cancer Center	New Haven	Connecticut	United States	06510

Sponsors and Collaborators

• Yale University

Investigators

• Principal Investigator: Jeremy S. Kortansky, M.D., Yale University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 20, 2020
• Informed Consent Form - Jun 21, 2019

More Information

Publications

None provided.

• Responsible Party: Yale University
• ClinicalTrials.gov Identifier: NCT02848079
• Other Study ID Numbers: 1605017852
• First Posted: Jul 28, 2016
• Last Update Posted: Jul 20, 2021
• Last Verified: Jun 1, 2021

• Additional relevant MeSH terms: Colorectal Neoplasms

Study Results

Participant Flow

Arm/Group Title	Combined TAS-102 and TAS-OX
Arm/Group Description	Combination treatment with TAS-102 and oxaliplatin. TAS-102 is an oral medication; oxaliplatin (TAS-OX) is given by infusion. In Part 1 treatments were started at level 1 doses, which were based on prior clinical experience with the medications studied. Dose escalation followed a traditional "3+3" design. The subjects in Part 2 were treated with dose level 3. Oxaliplatin infusion was given on day 1 of each cycle. TAS-102 was taken twice daily on days 1-5 of each cycle.
Period Title: Overall Study
STARTED	41
Receieved Study Treatment	41
Discontinued	41
COMPLETED	41
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Combined TAS-102 and TAS-OX
Arm/Group Description	Combination treatment with TAS-102 and oxaliplatin. TAS-102 is an oral medication; oxaliplatin (TAS-OX) is given by infusion.
Overall Participants	41
Age, Customized (years) [Median (Full Range) ]
Median (Full Range) [years]	62
Sex: Female, Male (Count of Participants)
Female	15 36.6%
Male	26 63.4%
Race/Ethnicity, Customized (Count of Participants)
White	38 92.7%
Black	1 2.4%
Asian	2 4.9%
ECOG (Count of Participants)
0	25 61%
1	16 39%
Location of primary tumor, No. (Count of Participants)
Left side of colon, including rectum	31 75.6%
Right side of colon	10 24.4%
Stage at diagnosis (Count of Participants)
I	1 2.4%
II	2 4.9%
III	13 31.7%
IV	25 61%
Histology (Count of Participants)
Well-differentiated	2 4.9%
Moderately differentiated	30 73.2%
Poorly differentiated	9 22%
High microsatellite instability (Count of Participants)
Count of Participants [Participants]	2 4.9%
KRAS/BRAF mutation (Count of Participants)
KRAS mutation	20 48.8%
BRAF mutation	1 2.4%
Wild type	20 48.8%
Number of prior therapies (Count of Participants)
1 therapy	1 2.4%
2 therapies	18 43.9%
3 therapies	15 36.6%
≥ 4 therapies	7 17.1%
Progression during prior oxaliplatin (Count of Participants)
Yes	18 43.9%
No	23 56.1%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate
Description	Overall Response Rate was measured by Response Evaluation Criteria In Solid Tumor (RECIST) 1.1 criteria. Tumors were assessed with CT or MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.".
Time Frame	up to 30 days following discontinuation of treatment

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT)

Arm/Group Title	Combined TAS-102 and TAS-OX
Arm/Group Description	Combination treatment with TAS-102 and oxaliplatin. TAS-102 is an oral medication; oxaliplatin (TAS-OX) is given by infusion.
Measure Participants	41
Median (95% Confidence Interval) [months]	2.4

2. Secondary Outcome

Title	Progression Free Survival
Description	Progression Free Survival was assessed according to RECIST criteria version 1.1. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time Frame	from the date of start of treatment to the date of first documented progression or any cause of death assessed up to 12 months.

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT)

Arm/Group Title	Combined TAS-102 and TAS-OX
Arm/Group Description	Combination treatment with TAS-102 and oxaliplatin. TAS-102 is an oral medication; oxaliplatin (TAS-OX) is given by infusion.
Measure Participants	41
Median (95% Confidence Interval) [months]	2.7

3. Secondary Outcome

Title	Overall Survival
Description	Overall Survival was assessed by the time to death from start of study.
Time Frame	from the date of start of treatment to the date of any cause of death assessed up to 24 months.

Outcome Measure Data

Analysis Population Description

Intention-to-Treat (ITT)

Arm/Group Title	Combined TAS-102 and TAS-OX
Arm/Group Description	Combination treatment with TAS-102 and oxaliplatin. TAS-102 is an oral medication; oxaliplatin (TAS-OX) is given by infusion.
Measure Participants	41
Median (95% Confidence Interval) [months]	6.8

Adverse Events

Time Frame	up to 38 months
Adverse Event Reporting Description	The reported AEs here are all AEs in the study, regardless of attribution. Whereas in the published manuscript, SAE's were reported when they could be attributed to treatment and that a 10% threshold was used in reporting AE's.
Arm/Group Title	Combined TAS-102 and TAS-OX
Arm/Group Description	Combination treatment with TAS-102 and oxaliplatin. TAS-102 is an oral medication; oxaliplatin (TAS-OX) is given by infusion.
All Cause Mortality
	Combined TAS-102 and TAS-OX
	Affected / at Risk (%)	# Events
Total	37/41 (90.2%)
Serious Adverse Events
	Combined TAS-102 and TAS-OX
	Affected / at Risk (%)	# Events
Total	8/41 (19.5%)
Gastrointestinal disorders
Ascites	1/41 (2.4%)
General disorders
Fever	1/41 (2.4%)
General disorders and administration site conditions - Other, specify	1/41 (2.4%)
Hepatobiliary disorders
Hepatobiliary disorders - Other, specify	1/41 (2.4%)
Infections and infestations
Infections and infestations - Other, specify	1/41 (2.4%)
Injury, poisoning and procedural complications
Fracture	1/41 (2.4%)
Renal and urinary disorders
Renal and urinary disorders - Other, specify	1/41 (2.4%)
Respiratory, thoracic and mediastinal disorders
Respiratory, thoracic and mediastinal disorders - Other, specify	1/41 (2.4%)
Vascular disorders
Thromboembolic event	2/41 (4.9%)
Other (Not Including Serious) Adverse Events
	Combined TAS-102 and TAS-OX
	Affected / at Risk (%)	# Events
Total	41/41 (100%)
Blood and lymphatic system disorders
Anemia	25/41 (61%)	46
Platelet count decrease	13/41 (31.7%)
Alkaline phosphatase increased	20/41 (48.8%)	28
Blood and lymphatic system disorders - Other, specify	8/41 (19.5%)	24
Gastrointestinal disorders
Diarrhea	9/41 (22%)
Vomiting	12/41 (29.3%)	20
Abdominal Pain	11/41 (26.8%)	14
Constipation	11/41 (26.8%)	19
Diarrhea	13/41 (31.7%)	24
Flatulence	3/41 (7.3%)	3
Nausea	22/41 (53.7%)	39
General disorders
Anorexia	16/41 (39%)	21
Fatigue	27/41 (65.9%)	48
Fever	4/41 (9.8%)	6
Pain	3/41 (7.3%)	5
Edema limbs	6/41 (14.6%)	8
Infusion related reaction	3/41 (7.3%)	3
Infections and infestations
Sinusitis	3/41 (7.3%)	3
Investigations
Neutrophil count decrease	15/41 (36.6%)	49
White blood cell decreased	14/41 (34.1%)	51
Alanine aminotransferase increased	9/41 (22%)	12
Aspartate aminotransferase increased	14/41 (34.1%)	22
Blood bilirubin increased	10/41 (24.4%)	22
Creatinine increased	3/41 (7.3%)	3
INR increased	4/41 (9.8%)	11
Lymphocyte count decreased	15/41 (36.6%)	49
Platelet count decreased	17/41 (41.5%)	59
Weight Loss	4/41 (9.8%)	5
Metabolism and nutrition disorders
Hypoalbuminemia	11/41 (26.8%)	17
Hypocalcemia	7/41 (17.1%)	8
Hypokalemia	7/41 (17.1%)	9
Hyponatremia	12/41 (29.3%)	17
Hypophosphatemia	5/41 (12.2%)	7
Musculoskeletal and connective tissue disorders
Back Pain	3/41 (7.3%)	3
Nervous system disorders
Peripheral sensory neuropathy	6/41 (14.6%)
Dizziness	6/41 (14.6%)	7
Dysgeusia	7/41 (17.1%)	7
Headache	3/41 (7.3%)	3
Paresthesia	8/41 (19.5%)	13
Peripheral sensory neuropathy	17/41 (41.5%)	24
Psychiatric disorders
Insomnia	7/41 (17.1%)	9
Respiratory, thoracic and mediastinal disorders
Cough	9/41 (22%)	12
Dyspnea	8/41 (19.5%)	9
Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue disorders - Other, specify	3/41 (7.3%)	3
Vascular disorders
Hypertension	12/41 (29.3%)	23

Limitations/Caveats

[Not Specified]

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.