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Neoadjuvant Therapy in Rectal CancerPhase 1PRAER 1NCT03152370

Preoperative Radiotherapy and E7046 in Rectum Cancer

A Phase 1 study testing E7046, Long Course Chemoradiotherapy (LCRT) and Short Course Radiotherapy (SCRT) in people with Neoadjuvant Therapy in Rectal Cancer, run by Adlai Nortye Biopharma Co., Ltd. at 5 sites in 3 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

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). Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Neoadjuvant Therapy in Rectal Cancer
What is being tested?
E7046, Long Course Chemoradiotherapy (LCRT) and Short Course Radiotherapy (SCRT)
Could I receive a placebo?
No, everyone receives an active treatment
How many people
29 participants
Where
5 sitesin 3 countries
Study dates
17 May 2017to 30 Sep 2021
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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  • 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

Who cannot join

  • 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.
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  • 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)

Trial locations and contacts

5 sites in 3 countries.

5 sites in 3 countries

United States2 sites

  • Massachusetts General Hospital

    Boston, Massachusetts, 02114

  • Weill Cornell

    New York, New York, 10065

Other trials in United States

United Kingdom2 sites

  • The Christie

    Manchester

  • Mount Vernon Hospital

    Northwood

Other trials in United Kingdom

Poland1 site

  • Marie-Skodowska Curie Cancer Centre

    Warsaw

Other trials in Poland

About this study

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

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.

Being tested
E7046, Long Course Chemoradiotherapy (LCRT), Short Course Radiotherapy (SCRT), capecitabine, folinic acid/5-FU/oxaliplatin (mFOLFOX-6)
Keywords
E7046, Radiotherapy/Chemoradiotherapy, Neoadjuvant therapy, Rectal cancer
Medical subject headings
Rectal Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • E7046Drug

    oral administration

  • Long Course Chemoradiotherapy (LCRT)Radiation

    pelvic radiotherapy

  • Short Course Radiotherapy (SCRT)Radiation

    pelvic radiotherapy

  • capecitabineDrug

    chemotherapy

  • folinic acid/5-FU/oxaliplatin (mFOLFOX-6)Drug

    chemotherapy

Study groups in NCT03152370
Study groupRoleWhat they receive
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.
Receives: Drug: E7046; Radiation: Long Course Chemoradiotherapy (LCRT); Drug: 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.
Receives: Drug: E7046; Radiation: Short Course Radiotherapy (SCRT); Drug: folinic acid/5-FU/oxaliplatin (mFOLFOX-6)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Determination of maximum tolerated dose (MTD) in combination with pre-operative chemoradiotherapy

    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).

    Measured: 10 weeks

  2. Number of participants with DLTs

    DLTs are defined as study drug-related toxicities meeting specified grades per the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 4.03.

    Measured: 10 weeks

  3. Number of participants with any serious adverse event (SAE)

    An SAE is any untoward medical occurrence that at any dose: results in death; is life threatening (ie, the participant was at immediate risk of death from the adverse event as it occurred; this does not include an event that, had it occurred in a more severe form or was allowed to continue, might have caused death); requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect (in the child of a participant who was exposed to the study drug).

    Measured: 10 weeks

  4. Number of participants with any non-serious adverse event (AE)

    An AE is any untoward medical occurrence in a patient or clinical investigation participant administered an investigational product. An AE does not necessarily have a causal relationship with the medicinal product.

    Measured: 10 weeks

Secondary outcomes (13)

  1. Pathological complete response (pCR) rate

    pCR is defined as the absence of any viable tumor cell on the resected specimen, irrespective of the proportions of necrosis and fibrosis.

    Measured: 14 to 16 weeks from the first dose of E7046

  2. Number of participants with a histopathologically confirmed circumferential margin negative (CRM-ve) resection

    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.

    Measured: 14 to 16 weeks from the first dose of E7046

  3. Number of participants with the indicated histopathologically confirmed tumor regression grade

    The pathologic tumor regression grade is defined as the tumor regression grade on posttreatment histopathological examination of the resection specimen.

    Measured: 14 to 16 weeks from the first dose of E7046

  4. Number of participants with the indicated magnetic resonance imaging (MRI)-confirmed tumor regression grade

    MRI-confirmed tumor regression grade is defined as the tumor regression grade on MRI images obtained after chemoradiotherapy.

    Measured: 11 to 13 weeks after the first dose of E7046

  5. Number of participants with the indicated MRI-confirmed down staging in T stage

    Downstaging in T stage is defined as a reduction in T stage after chemoradiotherapy on MRI images.

    Measured: 11 to 13 weeks after the first dose of E7046

  6. Disease-free survival (DFS)

    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.

    Measured: up to 2 years

  7. Mean maximum observed concentration (Cmax) for E7046 and its metabolite ER-888188 in plasma

    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

    Measured: Day 1, Day 8, Week 3, Week 7

  8. Mean time at which the highest drug concentration (Tmax) occurs for E7046 and its metabolite ER-888188 in plasma

    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

    Measured: Day 1, Day 8, Week 3, Week 7

  9. 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

    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

    Measured: Day 1, Day 8, Week 3, Week 7

  10. Mean area under the plasma concentration-time curve extrapolated to infinity (AUC0-inf) for E7046 and its metabolite ER-888188 in plasma

    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

    Measured: Day 1, Day 8, Week 3, Week 7

  11. Mean terminal elimination half-life (t1/2) of E7046 and its metabolite ER-888188 in plasma

    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

    Measured: Day 1, Day 8, Week 3, Week 7

  12. Mean accumulation ratio (Rac) of E7046 and its metabolite ER-888188 in plasma

    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

    Measured: Day 1, Day 8, Week 3, Week 7

  13. Mean peak-trough fluctuation (PTF) of E7046 and its metabolite ER-888188 in plasma

    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

    Measured: Day 1, Day 8, Week 3, Week 7

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted15 May 2017
  2. Study start17 May 2017
  3. Primary completion31 Aug 2021
  4. Study completion30 Sep 2021

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Model description
This study will investigate two neoadjuvant radiotherapy/chemoradiotherapy schedules in combination with E7046 in parallel.
Masking
None (open label)
Enrolment
29 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03152370
Sponsor's protocol ID
E7046-G000-102
Other IDs
2016-003064-38, 2016
Acronym
PRAER 1
Status last verified
Oct 2021
First submitted
11 May 2017
Last updated
4 Oct 2021
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing E7046, Long Course Chemoradiotherapy (LCRT) and Short Course Radiotherapy (SCRT) in people with Neoadjuvant Therapy in Rectal Cancer, run by Adlai Nortye Biopharma Co., Ltd. at 5 sites in 3 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 19 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 4 Oct 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 5 sites in United States, United Kingdom, Poland. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Determination of maximum tolerated dose (MTD) in combination with pre-operative chemoradiotherapy (time frame: 10 weeks). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03152370.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Oct 2021.

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