SPIRITT - Second-Line Panitumumab Irinotecan Treatment Trial

A Multi-center, Open-label, Randomized, Phase 2 Clinical Trial Evaluating Safety and Efficacy of FOLFIRI With Either Panitumumab or Bevacizumab as Second-Line Treatment in Subjects With Metastatic Colorectal Cancer With Wild-type KRAS Tumors

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00418938

Enrollment

266

Registered

2007-01-05

Start date

2006-11-01

Completion date

2013-04-01

Last updated

2018-10-17

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Cancer, Colon Cancer, Colorectal Cancer, Metastatic Cancer, Metastatic Colorectal Cancer, Rectal Cancer

Keywords

EGFR, FOLFIRI, 2nd Line Therapy, 2nd Line mCRC Therapy, mCRC, Irinotecan, panitumumab, bevacizumab

Brief summary

This is a multi-center, open-label, randomized, phase 2, two-arm clinical trial to be conducted in the United States. Approximately 210 eligible KRAS wild-type expressing metastatic colorectal cancer subjects who have failed first-line oxaliplatin-based chemotherapy (with at least 4 doses of oxaliplatin-based chemotherapy) with at least 4 doses of bevacizumab (failure is defined as toxicity due to oxaliplatin-based chemotherapy or progression of disease on first-line treatment) will be randomized in a 1:1 ratio to receive either a once-every-two-weeks (Q2W) FOLFIRI regimen plus panitumumab 6 mg/kg or a Q2W FOLFIRI regimen plus bevacizumab (either 5 mg/kg or 10 mg/kg, depending on physician choice and institutional standard of care).

Detailed description

This phase 2, multicenter, open-label, randomized, two-arm study was designed to estimate the treatment effect of panitumumab in combination with FOLFIRI compared to bevacizumab in combination with FOLFIRI in subjects with metastatic colorectal cancer (mCRC) who had failed first-line therapy with at least 4 doses of oxaliplatin-based chemotherapy and bevacizumab. After data became available demonstrating that the treatment effect of antiepidermal growth factor receptor (EGFR) agents was limited to patients with wild-type Kirsten rat Sarcoma-2 virus (KRAS) mCRC, the study was amended to enroll only subjects with wild-type KRAS tumors. Eligible subjects were randomized in a 1:1 ratio to receive panitumumab 6 mg/kg plus FOLFIRI once every 2 weeks (Q2W) or bevacizumab 5 mg/kg or 10 mg/kg plus FOLFIRI Q2W. Randomization was stratified by the reason for first-line treatment failure (progression vs toxicity) and by intended bevacizumab dose (5 mg/kg vs 10 mg/kg). The intended bevacizumab doses were ascertained from sites at the time of site initiation. Subjects were treated with all or any components of second-line treatment until the occurrence of unacceptable adverse events, disease progression, death, loss to follow up, or study withdrawal by the subject, investigator, or sponsor. Tumor response was evaluated by blinded central radiology review per modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 and by the investigator using either modified RECIST version 1.0 or clinical assessment. After subjects permanently discontinued all components of second-line treatment, they were to undergo a safety follow-up assessment 30 (± 7) days after the last dose. Subjects ending second-line treatment before disease progression were followed for PFS (radiographic disease assessment) every 12 weeks (± 14 days) from the safety follow-up visit until disease progression, initiation of a new therapy for mCRC, or until approximately 100 PFS events were observed in subjects with wild-type KRAS tumors. Subjects were also followed for survival every 12 weeks (± 14 days) from the safety follow-up assessment until approximately 100 PFS events were observed in subjects with wild-type KRAS tumors.

Interventions

DRUGPanitumumab

6mg/kg IV

DRUGBevacizumab

Either 5mg/kg OR 10mg/kg IV

DRUGLeucovorin

400mg/m\^2 IV (in the vein)

DRUGIrinotecan

180mg/m\^2 IV (in the vein)

DRUG5-Fluorouracil

400mg/m\^2 bolus IV (in the vein) over 2-4 min, followed by 2400mg/m\^2 continuous IV over 46 hours for the first 2 cycles, increased to 3000mg/m\^2 thereafter if no significant side effects

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Diagnosis of metastatic adenocarcinoma of the colon or rectum that cannot, in the opinion of the investigator, be cured by surgical resection at the time of randomization * Wild-type KRAS expressing mCRC from the primary tumor or metastasis. * Failure of prior first-line oxaliplatin-based chemotherapy with bevacizumab (at least four therapeutic doses of oxaliplatin-based chemotherapy and bevacizumab) for mCRC. * At least one uni-dimensionally measurable lesion per modified RECIST criteria. * Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Man or woman 18 years of age or older * Hematology, chemistry, coagution, metabolic functions within normal or protocol-defined limits

Exclusion criteria

* Previous irinotecan, anti-EGFr therapy (eg, cetuximab, panitumumab, erlotinib, gefitinib, lapatinib) or vaccine for the treatment of mCRC * Radiotherapy ≤ 14 days before randomization * Evidence of central nervous system (CNS) metastases * Unresolved toxicities from prior anti-cancer therapy that, in the opinion of the investigator, precludes subject from participation * History of other invasive primary cancer, except: * Curatively resected or treated non-melanomatous skin cancer * Curatively treated cervical carcinoma in situ * Other primary solid tumor treated curatively and no treatment administered ≤ 2 years before randomization and, in the investigator's opinion, it is unlikely that there will be a recurrence ≤ 2 years post randomization Medications * C hronic daily treatment (as determined by the investigator) with aspirin (\> 325 mg/day) or non steroidal anti inflammatory agents known to inhibit platelet function * Infection requiring a course of systemic anti-infectives that was completed ≤ 14 days before randomization (exception can be made at the judgment of the investigator for oral treatment of an uncomplicated urinary tract infection \[UTI\]) * Subjects concurrently receiving any investigational agent or therapy ≤ 30 days before randomization General: * Significant cardiovascular risk as defined by the protocol * History of peripheral arterial ischemia ≤ 24 weeks before randomization (subjects with brief, reversible, exercise-induced claudication are eligible) * History of visceral arterial ischemia ≤ 24 weeks before randomization * Significant bleeding risk: * Major surgical procedure, open biopsy, or significant traumatic injury ≤ 28 days before randomization * Anticipation of need for major surgical procedures during the course of the study * C ore biopsy or other minor procedure, excluding placement of a vascular access device ≤ 7 days before randomization * A ny significant bleeding that is not related to the primary colon tumor ≤ 24 weeks before randomization * P re-existing bleeding diathesis or coagulopathy with the exception of well-controlled chronic anticoagulation therapy * Serious or non-healing wounds, skin ulcers, or unhealed bone fractures * Gastroduodenal ulcer(s) determined by endoscopy to be active or uncontrolled gastrointestinal ulcer ≤ 28 days before randomization * History of interstitial lung disease (eg, pneumonitis or pulmonary fibrosis) or evidence of interstitial lung disease on baseline chest x-ray (CXR) or computed tomography (CT) scan * Clinically significant ascites * Subjects known to be human immunodeficiency virus (HIV) positive or known to have chronic or active hepatitis B or C infection * Men and women of childbearing potential (women who are post-menopausal \< 52 weeks, not surgically sterilized, or not abstinent) who do not consent to use adequate contraception (according to institutional standard of care) during the course of the study and after the last date of receiving second-line treatment (24 weeks for women, 4 weeks for men) * Women who test positive for serum or urine pregnancy test ≤ 72 hours before randomization or are breast-feeding * Subjects allergic to any component that is part of the treatment regimen

Design outcomes

Primary

Measure	Time frame	Description
Progression-free Survival (PFS)	From randomization up to 65 months.	Progression-free survival is defined as time from the date of randomization to the date of first progression per modified RECIST version 1.0 (based on central review of the radiographic scans), or death within 60 days after the last evaluable tumor assessment or randomization date (whichever is later).

Secondary

Measure	Time frame	Description
Disease Control	From randomization up to 65 months.	Disease control is defined as incidence of objective response or stable disease on study up to starting a new anti-tumor therapy.
Objective Response Rate	From randomization up to 65 months.	Objective response rate is defined as incidence of either a confirmed complete response (CR) or partial response (PR) on study up to starting a new anti-tumor therapy and will be based on modified RECIST version 1.0 (responder) by central assessment.
Overall Survival	From randomization up to 65 months.	Overall survival is defined as time from the date of randomization to the date of death due to any cause. Subjects who have not died or are lost to follow-up at the analysis cutoff date will be censored at their last contact date.
Time to Progression	From randomization up to 65 months.	Time to progression is defined as time from the date of randomization to the date of radiographic disease progression per modified RECIST version 1.0 (per central assessment).
Duration of Response	From randomization up to 65 months.	Duration of response is defined as time from first confirmed objective response to disease progression per modified RECIST version 1.0 (by central assessment).
Time to Response	From randomization up to 65 months.	Time to response is defined as time from the date of randomization to the date of first confirmed objective response

Participant flow

Pre-assignment details

We enrolled 266 subjects, but we only perform analyses on the Full Analysis Set, defined as all randomized subjects who provide informed consent before the initiation of any study specific procedures and who receive at least one dose of panitumumab or bevacizumab. There are 264 patients in this Full Analysis Set.

Participants by arm

Arm	Count
Panitumumab Plus FOLFIRI subjects in this arm receive once-every-2-weeks (Q2W) FOLFIRI regimen plus panitumumab 6 mg/kg	133
Bevacizumab Plus FOLFIRI subjects in this arm receive once-every-2-weeks (Q2W) FOLFIRI regimen plus bevacizumab (either 5 mg/kg or 10 mg/kg, depending on physician choice and institutional standard of care)	131
Total	264

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Administrative decision	3	3
Overall Study	Adverse Event	1	1
Overall Study	Ineligibility Determined	1	0
Overall Study	Lost to Follow-up	1	3
Overall Study	On-going	1	1
Overall Study	Reimbursement	1	0
Overall Study	Withdrawal by Subject	16	15

Baseline characteristics

Characteristic	Bevacizumab Plus FOLFIRI	Panitumumab Plus FOLFIRI	Total
Age, Continuous	59.1 years STANDARD_DEVIATION 9.9	59.9 years STANDARD_DEVIATION 11.6	59.5 years STANDARD_DEVIATION 10.8
Eastern Cooperative Oncology Group (ECOG) Performance Status 0 (Fully active)	70 Participants	74 Participants	144 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status 1 (Restricted in physically strenuous activity)	61 Participants	58 Participants	119 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status Missing	0 Participants	1 Participants	1 Participants
Number of metastatic organs 1	61 Participants	49 Participants	110 Participants
Number of metastatic organs 2	42 Participants	39 Participants	81 Participants
Number of metastatic organs >=3	28 Participants	44 Participants	72 Participants
Number of metastatic organs Missing	0 Participants	1 Participants	1 Participants
Primary tumor diagnosis Colon	91 Participants	102 Participants	193 Participants
Primary tumor diagnosis Rectum	40 Participants	31 Participants	71 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 Participants	1 Participants	1 Participants
Race/Ethnicity, Customized Asian	8 Participants	4 Participants	12 Participants
Race/Ethnicity, Customized Black or African American	18 Participants	21 Participants	39 Participants
Race/Ethnicity, Customized Hispanic or Latino	9 Participants	5 Participants	14 Participants
Race/Ethnicity, Customized Other	1 Participants	0 Participants	1 Participants
Race/Ethnicity, Customized White or Caucasian	95 Participants	102 Participants	197 Participants
Sex: Female, Male Female	46 Participants	46 Participants	92 Participants
Sex: Female, Male Male	85 Participants	87 Participants	172 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	133 / 133	129 / 131
serious Total, serious adverse events	61 / 133	39 / 131

Outcome results

Primary

Progression-free Survival (PFS)

Progression-free survival is defined as time from the date of randomization to the date of first progression per modified RECIST version 1.0 (based on central review of the radiographic scans), or death within 60 days after the last evaluable tumor assessment or randomization date (whichever is later).