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Phase 1b/II Trial of Pembrolizumab Plus IMRT in Stage III/IV Carcinoma of Anus (CORINTH)

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ClinicalTrials.gov Identifier: NCT04046133
Recruitment Status : Not yet recruiting
First Posted : August 6, 2019
Last Update Posted : August 6, 2019
Sponsor:
Information provided by (Responsible Party):
Cardiff University

Brief Summary:

The CORINTH trial is for patients with more advanced (stage 3 and 4) anal cancer. The numbers of patients with anal cancer is increasing and only 65% patients with this later stage anal cancer have not had a recurrence 3 years after treatment. Anal cancer responds well to chemo-radiation (CRT) and this would be the treatment used for standard clinical care. The chemotherapy in CORINTH will be the same as standard of care (Mitomycin and 5FU or capecitabine) and the radiotherapy (RT) will be delivered using a technique where the dose intensity of RT can be modulated for different areas of the tumor (Intensity Modulated RT - IMRT). Translational samples (tissue blocks and blood) will be collected at baseline with further blood and tissue samples during and after treatment.

Pembrolizumab, a relatively new drug, is a monoclonal antibody that enhances the body's immune response to cancer cells by acting on a receptor on the surface of T-cells called Programmed Death -1 (PD-1). The CORINTH study aims to see whether pembrolizumab, can be added safely to standard CRT. We will explore how safe the combination is and how well tolerated it is for patients with stage 3 and 4 anal cancer. If it is tolerable more patients will be treated to see if there is a similar or better clinical response.

The trial is designed in 3 groups of patients. All patients will receive eight infusions of pembrolizumab at three weekly intervals. Each infusion lasts approximately 1 hour. The first group will not get pembrolizumab until they have already had 4 weeks of CRT (Day 29). As long as this is not found to cause too many extra side effects, the next group will have infusions at the beginning of the third week of CRT. The final group (cohort 3) will start their pembrolizumab with the first day of CRT i.e. Day 1.

Initially each group will have 6 patients. Provided each group of patients finds the treatment tolerable and it is safe, more patients will be recruited into the group that receives the pembrolizumab earliest during their CRT. This will add further credence to the safety and tolerability of the combination and may provide a signal of how effective this treatment might be in improving outcomes for patients with more advanced anal cancer.


Condition or disease Intervention/treatment Phase
Anal Cancer Stage III A Anal Cancer Stage III B Drug: Pembrolizumab Phase 1

Detailed Description:

CORINTH is a multi center trial with a single arm. Patients will be recruited into 3 successive cohorts followed by an expansion of the final cohort. For each cohort the first dose of Pembrolizumab will be given at an earlier time point during the chemo-radiation (CRT).

Pemrolizumab will be given as an IV infusion every 21 days, and a total of 8 infusions per patient at 200mg per infusion. The first dose of Pemrolizumab will be given at the following times:

COHORT 1: beginning at Week 5 day 1 of CRT schedule COHORT 2: beginning at Week 3 day 1 of CRT schedule COHORT 3: beginning at Week 1 day 1 of CRT schedule** Cohort 2 will be dependent on a Safety Review Committee (SRC) recommendation. If the SRC are concerned about toxicity in Cohort 1 but not sufficiently to stop the study, they are able to recommend that Cohort 2 can change to commence pembrolizumab at week 4. If the SRC are concerned about toxicity in Cohort 2 but not sufficiently to stop the study, they are able to recommend that Cohort 3 can change to commence pembrolizumab at week 2.

Potential participants will be under the care of a consultant who specializes in the treatment of anal cancer and the patient will have been identified as requiring CRT treatment for their anal cancer. They will be assessed for eligibility before being consented and allocated to the current cohort. # Patients will be monitored for Adverse Events which will be assessed according to Common Terminology Criteria for Adverse Events (CTCAE) 4.03. Treatment guidelines are given for any immune related or infusion related events. Adverse Event review will take place weekly during CRT and at every Pembrolizumab visit as well as key time during follow up.

Patient reported outcomes will be assessed using the European Organisation for Research and Treatment of Cancer (EORTC) tool during CRT, pembrolizumab treatment and follow up. Patients will be followed up for 12 months.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1b/II Trial of Checkpoint Inhibitor (Pembrolizumab an Anti PD-1 Antibody) Plus Standard IMRT in HPV Induced Stage III/IV Carcinoma of Anus
Estimated Study Start Date : November 1, 2019
Estimated Primary Completion Date : November 30, 2022
Estimated Study Completion Date : November 30, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Anal Cancer

Arm Intervention/treatment
Experimental: pembrolizumab
Patients with locally advanced (stage IIIA/B, T3/T4, any N, M0) anal cancer will receive pembrolizumab, an immune checkpoint inhibitor, concomitantly with standard CRT.
Drug: Pembrolizumab
Pembrolizumab, an immune checkpoint inhibitor, concomitantly with standard CRT in patients with locally advanced T3/4 anal cancer.
Other Names:
  • Radiotherapy
  • Chemotherapy (Mytomycin or Mitomycin and Capecitabine)




Primary Outcome Measures :
  1. Safety and tolerability- 30 days post CRT [ Time Frame: 30 days post chemoradiotherapy ]
    To assess safety of different schedules of exposure to pembrolizumab, an immune checkpoint inhibitor, concomitantly with standard CRT in patients with locally advanced T 3/4 anal cancer. Grade 3 to 5 treatment related adverse events (CTCAE - v.4.03) will be reported at 30 days post chemoradiotherapy.

  2. Safety and tolerability- 6 weeks post CRT [ Time Frame: 6 weeks post chemoradiotherapy ]
    To assess the safety of different schedules of exposure to pembrolizumab, an immune checkpoint inhibitor, concomitantly with standard CRT in patients with locally advanced T3/4 anal cancer. Grade 3 to 5 treatment related adverse events (CTCAE v.4.03) will be reported at 6 weeks post chemoradiotherapy.

  3. Safety and tolerability - 12 weeks post CRT [ Time Frame: 12 weeks post chemoradiotherapy ]
    To assess the safety of different schedules of exposure to pembrolizumab, an immune checkpoint inhibitor, concomitantly with standard CRT in patients with locally advanced T3/4 anal cancer. Grade 3 to 5 treatment related adverse events (CTCAE v.4.03) will be reported at 12 weeks post chemoradiotherapy.

  4. Safety and tolerability - 6 months post CRT [ Time Frame: 6 months post chemoradiotherapy ]
    To assess the safety of different schedules of exposure to pembrolizumab, an immune checkpoint inhibitor, concomitantly with standard CRT in patients with locally advanced T3/4 anal cancer. Grade 3 to 5 treatment related adverse events (CTCAE v.4.03) will be reported at 6 months post chemoradiotherapy.

  5. Safety and tolerability- 9 months post CRT [ Time Frame: 9 months post chemoradiotherapy ]
    To assess the safety and of different schedules of exposure to pembrolizumab, an immune checkpoint inhibitor, concomitantly with standard CRT in patients with locally advanced T3/4 anal cancer. Grade 3 to 5 treatment related adverse events (CTCAE Adverse Events v.4.03) will be reported at 9 months post chemo-radiotherapy.

  6. Safety and tolerability- 12 months post CRT [ Time Frame: 12 months post chemoradiotherapy ]
    To assess the safety of different schedules of exposure to pembrolizumab, an immune checkpoint inhibitor, concomitantly with standard CRT in patients with locally advanced T3/4 anal cancer. Grade 3 to 5 treatment related adverse events (CTCAE v.4.03) will be reported at 12 months post chemoradiotherapy.


Secondary Outcome Measures :
  1. Adherence to protocol treatment [ Time Frame: Up to 6 months post chemoradiotherapy ]
    Adherence to protocol treatment will be assessed by numbers of patients receiving per protocol treatment, dose delays, treatment reductions, treatment discontinuation and documenting the reasons for delays or discontinuation for each patient.

  2. Recruitment [ Time Frame: 2 years ]
    Recruitment rate will be assessed by the number of days study is open for recruitment, the number of patients screened, the number of screened patients not recruited and why and the number (proportion) of patients recruited.

  3. Retention [ Time Frame: Up to 12 months post chemoradiotherapy ]
    Retention will be assessed by the proportion of patients withdrawing from protocol treatment and number of patients lost to follow-up with documentation of reasons in each case.

  4. Study eligibility [ Time Frame: 2 years ]
    Study eligibility will be assessed by the number of patients eligible and ineligible at screening and reasons for ineligibility.

  5. Clinical response assessment - 3 months post CRT [ Time Frame: 3 months post chemoradiotherapy ]
    Clinical response assessment will be measured by RECIST v 1.1 (MRI) for the overall response rate (ORR) at 3 months post chemoradiotherapy.

  6. Clinical response assessment - 6 months post CRT [ Time Frame: 6 months post chemoradiotherapy ]
    Clinical response assessment will be measured by RECIST v 1.1 (MRI) for the overall response rate (ORR) at 6 months post chemoradiotherapy.

  7. Clinical response assessment - 12 months follow up [ Time Frame: 12 months follow up ]
    Clinical response assessment will be measured by RECIST v 1.1 (MRI) for the overall response rate (ORR) at 12 months follow up

  8. Imaging response - 3 months post CRT [ Time Frame: 3 months post chemo-radiotherapy ]
    Imaging response will be assessed by Tumor Regression Grade MRI by changes in Apparent Diffusion Coefficient (ADC) on DW sequences. Immune related modified RECIST assessments (MRI) at 3 months post chemoradiotherapy.

  9. Imaging response - 6 months post CRT [ Time Frame: 6 months post chemoradiotherapy ]
    Imaging response will be assessed by Tumor Regression Grade MRI by changes in Apparent Diffusion Coefficient (ADC) on DW sequences. Immune related modified RECIST assessments (MRI) at 6 months post chemoradiotherapy.

  10. Imaging response - 12 months follow up [ Time Frame: 12 months follow up ]
    Imaging response will be assessed by Tumor Regression Grade MRI by changes in Apparent Diffusion Coefficient (ADC) on DW sequences. Immune related modified RECIST assessments (MRI) at 12 months follow up.

  11. Patient reported outcome - up to 6 months post CRT [ Time Frame: Up to 6 months post chemoradiotherapy ]
    Patient-reported outcomes (PRO) will be measured by using the EORTC quality of life questionnaires during CRT and 6 months post-CRT.

  12. Patient reported outcome - 12 months follow up [ Time Frame: 12 months follow up ]
    Patient-reported outcomes (PRO) will be measured by using the EORTC quality of life questionnaires at 12 months follow up



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

In order to be eligible for participation in this trial, the subject must:

  1. Be willing and able to provide written informed consent/assent for the trial.
  2. Age 18 years or over on day of signing informed consent.
  3. Histologically proven Squamous Cell Cancer of Anus (SCCA) Stage IIIA or IIIB (T3 / 4 any N M0) anal cancer or highly suspicious and confirmed by the MDT
  4. Be willing to provide tissue sample either archival or repeat biopsy to be tested for HPV and p16.
  5. Have a performance status of 0 or 1 on the ECOG Performance Scale.
  6. Demonstrate adequate organ function performed within 10 days of treatment initiation.
  7. Hematological: Absolute neutrophil count (ANC) ≥1.5 x 109/L, Platelets ≥100 x 109/L,
  8. Coagulation: International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN (unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants), Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN (unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants).
  9. Female subject of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
  10. Female subjects of childbearing potential must be willing to use an adequate method of contraception - Contraception and pregnancy, for the course of the study through 120 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
  11. Male subjects of childbearing potential must agree to use an adequate method of contraception - Contraception and pregnancy, starting with the first dose of study therapy through 120 days after the last dose of study therapy. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

Exclusion Criteria:

The subject must be excluded from participating in the trial if the subject:

  1. Has malignant tumour of non-epithelial origin (sarcoma)
  2. Has any metastatic disease
  3. Is unsuitable for radical CRT for whatever reason
  4. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
  5. Has a diagnosis of immunodeficiency (see 18. For patients with HIV who may be eligible) or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
  6. Has a known history of active TB (Bacillus Tuberculosis)
  7. Hypersensitivity to pembrolizumab or any of its excipients.
  8. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
  9. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.

    1. Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
    2. Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
  10. Has a known additional malignancy that is progressing 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 or in situ cervical cancer or previous VIN (vulval intra-epithelial neoplasia) or vulval cancer adequately treated, or previous adequately treated breast cancer / DCIS > 5 years ago.
  11. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  12. Has known history of, or any evidence of active, non-infectious pneumonitis.
  13. Has an active infection requiring systemic therapy.
  14. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
  15. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  16. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
  17. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
  18. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
  19. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
  20. 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 (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04046133


Contacts
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Contact: Margherita Carucci, PhD 004402920687900 caruccim@cardiff.ac.uk

Sponsors and Collaborators
Cardiff University
Investigators
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Principal Investigator: Marcia Hall, Dr Mount Vernon Cancer Centre
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Responsible Party: Cardiff University
ClinicalTrials.gov Identifier: NCT04046133    
Other Study ID Numbers: SPON 1529-16
First Posted: August 6, 2019    Key Record Dates
Last Update Posted: August 6, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Anus Neoplasms
Neoplasms
Rectal Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Anus Diseases
Rectal Diseases
Capecitabine
Pembrolizumab
Mitomycins
Mitomycin
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antineoplastic Agents, Immunological
Antibiotics, Antineoplastic
Alkylating Agents
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors