Clinical Trials /

Preoperative Radiotherapy and E7046 in Rectum Cancer

NCT03152370

Description:

This is a multicenter, open-label, Phase 1b study in participants with locally advanced rectum cancer where primary resection without chemoradiotherapy is unlikely to achieve clear margins as defined by magnetic resonance imaging (MRI). It is conducted to assess the safety, to assess the tolerability, and to determine the recommended Phase 2 dose (RP2D) of E7046 in combination with pre-operative chemoradiotherapy. The study will also assess the efficacy of the combination in the expansion part at RP2D.

Related Conditions:
  • Rectal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Preoperative Radiotherapy and E7046 in Rectum Cancer
  • Official Title: An Open-Label Multicenter Phase 1b Study of E7046 in Combination With Radiotherapy/Chemoradiotherapy (RT/CRT) in Preoperative Treatment of Subjects With Rectum Cancer

Clinical Trial IDs

  • ORG STUDY ID: E7046-G000-102
  • SECONDARY ID: 2016-003064-38
  • NCT ID: NCT03152370

Conditions

  • Neoadjuvant Therapy in Rectal Cancer

Interventions

DrugSynonymsArms
E7046E7046 in combination with Long Course Chemoradiotherapy (LCRT)
capecitabineE7046 in combination with Long Course Chemoradiotherapy (LCRT)
folinic acid/5-FU/oxaliplatin (mFOLFOX-6)E7046 in combination with SCRT followed by chemotherapy

Purpose

This is a multicenter, open-label, Phase 1b study in participants with locally advanced rectum cancer where primary resection without chemoradiotherapy is unlikely to achieve clear margins as defined by magnetic resonance imaging (MRI). It is conducted to assess the safety, to assess the tolerability, and to determine the recommended Phase 2 dose (RP2D) of E7046 in combination with pre-operative chemoradiotherapy. The study will also assess the efficacy of the combination in the expansion part at RP2D.

Trial Arms

NameTypeDescriptionInterventions
E7046 in combination with Long Course Chemoradiotherapy (LCRT)ExperimentalParticipants will receive once daily (QD) doses of E7046 (recommended Phase 2 dose [RP2D] determined in the Dose-Escalation part of the study) for 10 weeks, starting on Day 1, 14 days prior to initiation of the radiotherapy. LCRT will be initiated on Day 15 and will consist of a total of 45 Grays (GY) radiation administered in 1.8 GY daily doses delivered for 5 days (Monday to Friday) every week for 5 weeks. Capecitabine (825 milligrams per meters squared [mg/m^2]) will be administered twice daily on the days of radiotherapy. Surgery will be performed 14 to 16 weeks from the first day of E7046 treatment.
  • E7046
  • capecitabine
E7046 in combination with SCRT followed by chemotherapyExperimentalParticipants will receive QD doses of E7046 (RP2D determined in the Dose-Escalation part of the study) for 10 weeks, starting on Day 1, 14 days prior to initiation of the radiotherapy. Short course radiotherapy (SCRT) will be initiated on Day 15 and will consist of a total of 25 Gy radiation administered in 5 Gy daily doses for 5 days (Monday to Friday) for 1 week. Ten days after the end of radiotherapy, 3 cycles of the modified folinic acid/5-FU/oxaliplatin (mFOLFOX-6) regimen will be administered every 2 weeks for 2 consecutive days. Surgery will be performed 14 to 16 weeks from the first day of E7046 treatment.
  • E7046
  • folinic acid/5-FU/oxaliplatin (mFOLFOX-6)

Eligibility Criteria

        Inclusion Criteria:

          -  Diagnosis of histologically confirmed invasive primary rectal carcinoma

          -  Age ≥18 years at the time of informed consent

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

          -  Participants must have locally advanced rectum cancer where primary resection without
             chemoradiotherapy (CRT) is unlikely to achieve clear margins as defined by magnetic
             resonance imaging (MRI), with no metastatic disease, as assessed by independent
             review.

          -  Disease that can be encompassed within a radical radiotherapy treatment volume

          -  Participant must consent to repeated biopsy to allow the acquisition of fresh and/or
             formalin-fixed paraffin-embedded (FFPE) material. Available archived tumor material
             may be submitted as the pretreatment biopsy provided that minimum requirements are met
             by local pathology review as defined in the laboratory manual. If archived tumor
             material is not available or does not meet minimum requirements, then a fresh tumor
             biopsy must be obtained in accordance with local institutional practice.

          -  Adequate renal function defined as serum creatinine <1.5 × upper limit of normal (ULN)
             (or use System of Units [SI] units or calculated creatinine clearance ≥50 milliliter
             per minute [mL/min] per the Cockcroft and Gault formula)

          -  Adequate bone marrow function:

               -  Absolute neutrophil count (ANC) ≥1500/millimeters cubed (mm^3) (≥1.5 ×
                  10^3/microliters [µL])

               -  Platelets ≥100,000/mm^3 (≥100 × 10^9/Liters [L])

               -  Hemoglobin ≥9.0 grams per deciliter (g/dL)

          -  Adequate liver function:

               -  Adequate blood coagulation function as evidenced by an International Normalized
                  Ratio (INR) ≤1.5

               -  Total bilirubin ≤1.5 × ULN except for unconjugated hyperbilirubinemia or
                  Gilbert's syndrome

               -  Alkaline phosphatase, alanine aminotransferase (ALT), and aspartate
                  aminotransferase (AST) ≤2.5 × ULN

          -  No prior pelvic radiotherapy, chemotherapy, immunotherapy, or other anti-cancer
             treatment for rectal cancer

          -  No prior exposure to colony stimulating factor 1 receptor (CSF1R) antagonists such as
             but not limited to emactuzumab (RG7155) (Roche), PLX3397 (Plexicon), JNJ40346627
             (Johnson & Johnson), including both anti-CSF1R and small molecule inhibitors and
             prostaglandin E2 receptor 4 (EP4) antagonists

          -  No preexisting condition that would deter radiotherapy, eg, fistulas, severe
             ulcerative colitis (particularly participants currently taking sulphasalazine),
             Crohn's disease, prior adhesions

          -  Willing and able to give informed consent and comply with all aspects of the protocol

        Exclusion Criteria:

          -  Any contraindications to MRI (eg, participants with pacemakers, claustrophobia,
             excessive weight, etc).

          -  Unfit to receive study treatment or subsequent surgical resection

          -  Active hydronephrosis

          -  Unequivocal evidence of metastatic disease defined by computerized tomography (CT)
             (includes resectable metastases)

          -  Prolongation of corrected QT (QTc) interval to >480 milliseconds (msec) when
             electrolyte balance is normal

          -  Recent occurrence (within 3 to 6 months) of a major thromboembolic event, such as
             pulmonary embolism or proximal deep vein thrombosis, unless stable on (>1 month)
             therapeutic anticoagulation (aspirin <325 milligrams (mg) daily or
             low-molecular-weight heparin [LMWH]). Participants with a history of clinically
             non-significant thromboembolic events, not requiring anticoagulation, are allowed on
             study.

          -  Participants receiving oral warfarin are not eligible for this study (unless warfarin
             is discontinued at least 7 days prior to commencement of treatment and for the
             duration of the study, or oral warfarin is converted to LMWH, where local clinical
             opinion considers this an acceptable option).

          -  Previous radiotherapy in the pelvic region (eg, prostate) or previous rectal surgery
             (eg, total mesorectal excision [TME]) or any investigational treatment for rectal
             cancer

          -  Cardiac conditions as follows: uncontrolled hypertension (resting blood pressure [BP]
             ≥150/95 millimeters of mercury [mmHg] despite optimal therapy), heart failure New York
             Heart Association (NYHA) Class II or above, prior or current cardiomyopathy, atrial
             fibrillation with heart rate >100 beats per minute (bpm). Unstable ischemic heart
             disease (myocardial infarction within 6 months prior to starting treatment, or angina
             requiring use of nitrates more than once weekly)

          -  Has a known additional malignancy that is progressing and/or requires active
             treatment. Exceptions include basal cell carcinoma of the skin or squamous cell
             carcinoma of the skin that has undergone potentially curative therapy, previous ductal
             carcinoma in situ (DCIS), or breast cancer diagnosed more than 5 years ago, as long as
             adequately treated or in situ, or early (up to stage 1B1) cervical cancer, or vulval
             intraepithelial neoplasia (VIN), or vulval cancer adequately treated without pelvic
             radiation therapy (RT)

          -  Refractory nausea and vomiting, chronic gastrointestinal diseases (eg, inflammatory
             bowel disease), or significant bowel resection that may impair adequate absorption and
             bioavailability of study drug. Major disturbance of bowel function (eg, gross fecal
             incontinence or requiring >6 mg loperamide each day).

          -  Participants with prior Hepatitis B or C infection with inadequate liver function

          -  Recent major surgery within 4 weeks prior to entry into the study (excluding the
             placement of vascular access and defunctioning stoma or any other surgical procedures
             not considered major by the investigator) that would prevent administration of study
             treatment

          -  Known dihydropyrimidine dehydrogenase (DPD) deficiency

          -  Participants with progressive neurological dysfunction that would confound the
             evaluation of neurological and other toxicities; any evidence of severe or
             uncontrolled systemic disease, active infection, active bleeding diatheses or renal
             transplant, including any participant with known active hepatitis B, hepatitis C, or
             human immunodeficiency virus (HIV) infection

          -  Participants with interstitial pneumonia or extensive and symptomatic fibrosis of the
             lungs

          -  Participants with any active autoimmune disease or a documented history of autoimmune
             disease, poorly controlled asthma or history of syndrome that required systemic
             steroids or immunosuppressive medications, except for participants with vitiligo or
             resolved childhood asthma/atopy. Participants with asthma who require intermittent use
             of bronchodilators (such as albuterol) will not be excluded from this study.

          -  Any other major illness that, in the investigator's judgment, will substantially
             increase the risk associated with the participant's participation in this study

          -  Has received a live vaccine within 30 days of planned start of study therapy. Note:
             Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
             are allowed; however, intranasal influenza vaccines (eg, Flu-Mist®) are live
             attenuated vaccines, and are not allowed.

          -  Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a
             negative beta-human chorionic gonadotropin [β-hCG] test with a minimum sensitivity of
             25 International Units per Liter [IU/L] or equivalent units of ß-hCG). A separate
             baseline assessment is required if a negative screening pregnancy test was obtained
             more than 72 hours before the first dose of study drug. Females of childbearing
             potential (all females will be considered to be of childbearing potential unless they
             are postmenopausal [amenorrheic for at least 12 consecutive months, in the appropriate
             age group, and without other known or suspected cause] or have been sterilized
             surgically [ie, bilateral tubal ligation, total hysterectomy, or bilateral
             oophorectomy, all with surgery at least 1 month before dosing]) who:

               -  Had unprotected sexual intercourse within 30 days before study entry and who do
                  not agree to use a highly effective method of contraception (eg, true abstinence
                  if it is their preferred and usual lifestyle [defined as refraining from
                  heterosexual intercourse during the entire period of risk associated with the
                  study treatments], an intrauterine device, a contraceptive implant, an oral
                  contraceptive, or have a vasectomized partner with confirmed azoospermia)
                  throughout the entire study period and for 6 months after study drug
                  discontinuation;

               -  Are not currently abstinent or do not agree to refrain from sexual activity
                  during the study period and for 6 months after study drug discontinuation;

               -  Are using hormonal contraceptives but are not on a stable dose of the same
                  hormonal contraceptive product for at least 4 weeks before dosing and who do not
                  agree to use the same contraceptive during the study or for 6 months after study
                  drug discontinuation.

          -  Males who have not had a successful vasectomy (confirmed azoospermia) or they and
             their female partners do not meet the criteria above (ie, not of childbearing
             potential or practicing highly effective contraception throughout the study period or
             for 6 months after study drug discontinuation)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Determination of maximum tolerated dose (MTD) in combination with pre-operative chemoradiotherapy
Time Frame:10 weeks
Safety Issue:
Description:The MTD is defined as one dose level below the dose level where ≥2 of 6 participants experience a dose-limiting toxicity (DLT; study drug-related toxicity) (ie, ≥33% of participants with a DLT at that dose level).

Secondary Outcome Measures

Measure:Pathological complete response (pCR) rate
Time Frame:14 to 16 weeks from the first dose of E7046
Safety Issue:
Description:pCR is defined as the absence of any viable tumor cell on the resected specimen, irrespective of the proportions of necrosis and fibrosis.
Measure:Number of participants with a histopathologically confirmed circumferential margin negative (CRM-ve) resection
Time Frame:14 to 16 weeks from the first dose of E7046
Safety Issue:
Description:The circumferential resection margin in rectal cancer has been defined as the non-peritonealized surface of a resection specimen created by dissection of the subperitoneal aspect at surgery.
Measure:Number of participants with the indicated histopathologically confirmed tumor regression grade
Time Frame:14 to 16 weeks from the first dose of E7046
Safety Issue:
Description:The pathologic tumor regression grade is defined as the tumor regression grade on posttreatment histopathological examination of the resection specimen.
Measure:Number of participants with the indicated magnetic resonance imaging (MRI)-confirmed tumor regression grade
Time Frame:11 to 13 weeks after the first dose of E7046
Safety Issue:
Description:MRI-confirmed tumor regression grade is defined as the tumor regression grade on MRI images obtained after chemoradiotherapy.
Measure:Number of participants with the indicated MRI-confirmed down staging in T stage
Time Frame:11 to 13 weeks after the first dose of E7046
Safety Issue:
Description:Downstaging in T stage is defined as a reduction in T stage after chemoradiotherapy on MRI images.
Measure:Disease-free survival (DFS)
Time Frame:up to 2 years
Safety Issue:
Description:Disease-free survival is defined as the time from treatment start to the date of the first documented disease occurrence, or date of death, whichever occurs first.
Measure:Mean maximum observed concentration (Cmax) for E7046 and its metabolite ER-888188 in plasma
Time Frame:Day 1, Day 8, Week 3, Week 7
Safety Issue:
Description:Dose-Escalation: Day 1 and Day 8 at predose (0 hours [hr]); 0.5, 1, 2, 4, 6, 8, 10, and 24 hr postdose. Week 3 and Week 7 at predose; 0.5 to 4 hr and 8 to 12 hr postdose (from participants on E7046 treatment). Expansion Cohort: Day 1 and Day 8 at predose; 0.5 to 4 hr and 8 to 12 hr postdose. Week 3 and Week 7 at predose; 0.5 to 4 hr and 8 to 12 hr postdose
Measure:Mean time at which the highest drug concentration (Tmax) occurs for E7046 and its metabolite ER-888188 in plasma
Time Frame:Day 1, Day 8, Week 3, Week 7
Safety Issue:
Description:Dose-Escalation: Day 1 and Day 8 at predose (0 hr); 0.5, 1, 2, 4, 6, 8, 10, and 24 hr postdose. Week 3 and Week 7 at predose; 0.5 to 4 hr and 8 to 12 hr postdose (from participants on E7046 treatment). Expansion Cohort: Day 1 and Day 8 at predose; 0.5 to 4 hr and 8 to 12 hr postdose. Week 3 and Week 7 at predose; 0.5 to 4 hr and 8 to 12 hr postdose
Measure:Mean area under the concentration-time curve from zero time to time of last quantifiable concentration (AUC[0-t]) for E7046 and its metabolite ER-888188 in plasma
Time Frame:Day 1, Day 8, Week 3, Week 7
Safety Issue:
Description:Dose-Escalation: Day 1 and Day 8 at predose (0 hr); 0.5, 1, 2, 4, 6, 8, 10, and 24 hr postdose. Week 3 and Week 7 at predose; 0.5 to 4 hr and 8 to 12 hr postdose (from participants on E7046 treatment). Expansion Cohort: Day 1 and Day 8 at predose; 0.5 to 4 hr and 8 to 12 hr postdose. Week 3 and Week 7 at predose; 0.5 to 4 hr and 8 to 12 hr postdose
Measure:Mean area under the plasma concentration-time curve extrapolated to infinity (AUC0-inf) for E7046 and its metabolite ER-888188 in plasma
Time Frame:Day 1, Day 8, Week 3, Week 7
Safety Issue:
Description:Dose-Escalation: Day 1 and Day 8 at predose (0 hr); 0.5, 1, 2, 4, 6, 8, 10, and 24 hr postdose. Week 3 and Week 7 at predose; 0.5 to 4 hr and 8 to 12 hr postdose (from participants on E7046 treatment). Expansion Cohort: Day 1 and Day 8 at predose; 0.5 to 4 hr and 8 to 12 hr postdose. Week 3 and Week 7 at predose; 0.5 to 4 hr and 8 to 12 hr postdose
Measure:Mean terminal elimination half-life (t1/2) of E7046 and its metabolite ER-888188 in plasma
Time Frame:Day 1, Day 8, Week 3, Week 7
Safety Issue:
Description:Dose-Escalation: Day 1 and Day 8 at predose (0 hr); 0.5, 1, 2, 4, 6, 8, 10, and 24 hr postdose. Week 3 and Week 7 at predose; 0.5 to 4 hr and 8 to 12 hr postdose (from participants on E7046 treatment). Expansion Cohort: Day 1 and Day 8 at predose; 0.5 to 4 hr and 8 to 12 hr postdose. Week 3 and Week 7 at predose; 0.5 to 4 hr and 8 to 12 hr postdose
Measure:Mean accumulation ratio (Rac) of E7046 and its metabolite ER-888188 in plasma
Time Frame:Day 1, Day 8, Week 3, Week 7
Safety Issue:
Description:Dose-Escalation: Day 1 and Day 8 at predose (0 hr); 0.5, 1, 2, 4, 6, 8, 10, and 24 hr postdose. Week 3 and Week 7 at predose; 0.5 to 4 hr and 8 to 12 hr postdose (from participants on E7046 treatment). Expansion Cohort: Day 1 and Day 8 at predose; 0.5 to 4 hr and 8 to 12 hr postdose. Week 3 and Week 7 at predose; 0.5 to 4 hr and 8 to 12 hr postdose
Measure:Mean peak-trough fluctuation (PTF) of E7046 and its metabolite ER-888188 in plasma
Time Frame:Day 1, Day 8, Week 3, Week 7
Safety Issue:
Description:Dose-Escalation: Day 1 and Day 8 at predose (0 hr); 0.5, 1, 2, 4, 6, 8, 10, and 24 hr postdose. Week 3 and Week 7 at predose; 0.5 to 4 hr and 8 to 12 hr postdose (from participants on E7046 treatment). Expansion Cohort: Day 1 and Day 8 at predose; 0.5 to 4 hr and 8 to 12 hr postdose. Week 3 and Week 7 at predose; 0.5 to 4 hr and 8 to 12 hr postdose

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Adlai Nortye Biopharma Co., Ltd.

Trial Keywords

  • E7046
  • Radiotherapy/Chemoradiotherapy
  • Neoadjuvant therapy
  • Rectal cancer

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