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alloSHRINK - Standard cHemotherapy Regimen and Immunotherapy With Allogeneic NKG2D-based CYAD-101 Chimeric Antigen Receptor T-cells (alloSHRINK)

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ClinicalTrials.gov Identifier: NCT03692429
Recruitment Status : Recruiting
First Posted : October 2, 2018
Last Update Posted : December 3, 2018
Sponsor:
Collaborator:
Novella Clinical
Information provided by (Responsible Party):
Celyad (formerly named Cardio3 BioSciences)

Brief Summary:

This open-label Phase I study aims at assessing the safety, cell kinetics and clinical activity of the CYAD-101 treatment administered 3 times with a 2-week interval between each administration in metastatic colorectal cancer, concurrently with a standard chemotherapy treatment. The standard chemotherapy treatment consists in 6 consecutive cycles of FOLFOX, administered with a 2-week interval. The CYAD-101 treatment will be administered at a specific time point within the third, fourth and fifth chemotherapy cycles.

This Phase I study will contain two consecutive segments: a dose-escalation and an expansion segment:

The first segment (dose-escalation segment) will use a 3+3 design to determine the recommended dose of CYAD-101 on the basis of dose-limiting toxicities (DLTs).

The second segment (expansion segment) of the study will evaluate 3 injections of CYAD-101 at the recommended dose defined in the first segment, administered concurrently with FOLFOX, in a larger number of patients.


Condition or disease Intervention/treatment Phase
Colorectal Cancer Drug: CYAD-101 Phase 1

Detailed Description:

This open-label Phase I study aims at assessing the safety, cell kinetics and clinical activity of the CYAD-101 treatment administered 3 times with a 2-week interval between each administration in metastatic CRC, concurrently with a standard chemotherapy treatment. The standard chemotherapy treatment consists of 6 consecutive cycles of FOLFOX administered with a 2-week interval. The CYAD-101 treatment will start at Day 3 of the third chemotherapy cycle.

This Phase I study will contain two consecutive segments: a dose-escalation and an expansion segment:

The dose-escalation segment will evaluate the safety of three injections of CYAD-101 administered concurrently with FOLFOX in patients with metastatic CRC. A 3+3 design will be used to determine the recommended dose of CYAD-101.

The expansion segment of the study will then evaluate three injections of CYAD-101 at the RecD defined in the first segment, administered concurrently with FOLFOX, in a larger number of patients.

The Phase I dose-escalation segment will enroll a maximum of 18 patients (6 patients maximum per cohort in case of DLT) and the phase I expansion segment 18-21 additional patients. Patients from the dose escalation segment enrolled in the dose-level selected for expansion segment will be considered as part of the expansion segment for the statistical analyses. A maximum of 36 patients will be enrolled in the global Phase I study.

The only chemotherapy regimen accepted in this protocol is the FOLFOX (5-FU, leucovorin and oxaliplatin). This chemotherapy regimen is one of the recommended standard regimens for this stage. The FOLFOX regimen will be administered according to a two-week cycle schedule.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:
  1. st segment: The dose-escalation segment: All patients will be treated with 3 injections of CYAD-101. Three escalating dose-levels (1x10^8, 3x10^8 and 1x10^9 per injection) of CYAD-101 will be evaluated using a 3+3 design. Each CYAD-101 injection will be administered at Day 3, after 5-FU pump removal, of the chemotherapy cycles 3 to 5.

    • Cohort 1: 1x10^8 per injection
    • Cohort 2: 3x10^8 per injection
    • Cohort 3: 1x10^9 per injection
  2. nd segment: The expansion segment:

    • Cohort 4: The Recommended dose defined in the first segment, administered concurrently with FOLFOX, in a larger number of patients.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-label, Phase I Study to Assess the Safety, Cell Kinetics and Clinical Activity of Multiple Doses of CYAD-101, Administered Concurrently With the FOLFOX Treatment in Patients With Unresectable Metastatic Colorectal Cancer
Actual Study Start Date : November 28, 2018
Estimated Primary Completion Date : November 28, 2020
Estimated Study Completion Date : October 18, 2033

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Segment 1 Dose escalation Cohort 1

The treatment arms consist of 6 cycles. The chemotherapy cycles will be scheduled with a 2-week interval. Each cycle lasts 14 days and will be repeated every 15 days.

One cycle of FOLFOX consists of:

  • Oxaliplatin 85 mg/m² IV over 2 hours
  • Leucovorin 400 mg/m² (or L-folinic acid 200 mg/m²) IV over 2 hours
  • Fluorouracil 400 mg/m² IV bolus
  • Fluorouracil 2400 mg/m² IV over 46 hours

The CYAD-101 treatment at a dose of 1x10^8 will be administered at Day 3 of the third, the fourth and the fifth chemotherapy cycle.

Drug: CYAD-101
CYAD-101 has the potential to treat many of distinct tumor-types (solid and hematological). This Phase I study will explore the hypothesis that targeting of NKG2D-ligands with an allogeneic CAR T-cells, CYAD-101, concurrently with standard chemotherapy in patients with metastatic colorectal cancer is safe and might potentially improve the patients' outcome.
Other Names:
  • oxaliplatin 85 mg/m² IV over 2 hours
  • leucovorin 400 mg/m² IV over 2 hours
  • fluorouracil 400 mg/m² IV bolus
  • fluorouracil 2400 mg/m² IV over 46 hours

Experimental: Segment 1 Dose escalation Cohort 2

The treatment arms consist of 6 cycles. The chemotherapy cycles will be scheduled with a 2-week interval. Each cycle lasts 14 days and will be repeated every 15 days.

One cycle of FOLFOX consists of:

  • Oxaliplatin 85 mg/m² IV over 2 hours
  • Leucovorin 400 mg/m² (or L-folinic acid 200 mg/m²) IV over 2 hours
  • Fluorouracil 400 mg/m² IV bolus
  • Fluorouracil 2400 mg/m² IV over 46 hours

The CYAD-101 treatment at a dose of 3x10^8 will be administered at Day 3 of the third, the fourth and the fifth chemotherapy cycle.

Drug: CYAD-101
CYAD-101 has the potential to treat many of distinct tumor-types (solid and hematological). This Phase I study will explore the hypothesis that targeting of NKG2D-ligands with an allogeneic CAR T-cells, CYAD-101, concurrently with standard chemotherapy in patients with metastatic colorectal cancer is safe and might potentially improve the patients' outcome.
Other Names:
  • oxaliplatin 85 mg/m² IV over 2 hours
  • leucovorin 400 mg/m² IV over 2 hours
  • fluorouracil 400 mg/m² IV bolus
  • fluorouracil 2400 mg/m² IV over 46 hours

Experimental: Segment 1 Dose escalation Cohort 3

The treatment arms consist of 6 cycles. The chemotherapy cycles will be scheduled with a 2-week interval. Each cycle lasts 14 days and will be repeated every 15 days.

One cycle of FOLFOX consists of:

  • Oxaliplatin 85 mg/m² IV over 2 hours
  • Leucovorin 400 mg/m² (or L-folinic acid 200 mg/m²) IV over 2 hours
  • Fluorouracil 400 mg/m² IV bolus
  • Fluorouracil 2400 mg/m² IV over 46 hours

The CYAD-101 treatment at a dose of 1x10^9 will be administered at Day 3 of the third, the fourth and the fifth chemotherapy cycle.

Drug: CYAD-101
CYAD-101 has the potential to treat many of distinct tumor-types (solid and hematological). This Phase I study will explore the hypothesis that targeting of NKG2D-ligands with an allogeneic CAR T-cells, CYAD-101, concurrently with standard chemotherapy in patients with metastatic colorectal cancer is safe and might potentially improve the patients' outcome.
Other Names:
  • oxaliplatin 85 mg/m² IV over 2 hours
  • leucovorin 400 mg/m² IV over 2 hours
  • fluorouracil 400 mg/m² IV bolus
  • fluorouracil 2400 mg/m² IV over 46 hours

Experimental: Segment 1 Expansion Cohort 4

The treatment arms consist of 6 cycles. The chemotherapy cycles will be scheduled with a 2-week interval. Each cycle lasts 14 days and will be repeated every 15 days.

One cycle of FOLFOX consists of:

  • Oxaliplatin 85 mg/m² IV over 2 hours
  • Leucovorin 400 mg/m² (or L-folinic acid 200 mg/m²) IV over 2 hours
  • Fluorouracil 400 mg/m² IV bolus
  • Fluorouracil 2400 mg/m² IV over 46 hours

The CYAD-101 treatment at the recommended dose from the dose escalation phase will be administered at Day 3 of the third, the fourth and the fifth chemotherapy cycle.

Drug: CYAD-101
CYAD-101 has the potential to treat many of distinct tumor-types (solid and hematological). This Phase I study will explore the hypothesis that targeting of NKG2D-ligands with an allogeneic CAR T-cells, CYAD-101, concurrently with standard chemotherapy in patients with metastatic colorectal cancer is safe and might potentially improve the patients' outcome.
Other Names:
  • oxaliplatin 85 mg/m² IV over 2 hours
  • leucovorin 400 mg/m² IV over 2 hours
  • fluorouracil 400 mg/m² IV bolus
  • fluorouracil 2400 mg/m² IV over 46 hours




Primary Outcome Measures :
  1. Dose Escalation Segment: The occurrence of Dose Limiting Toxicities in all patients during the study treatment until 14 days after the last CYAD-101 study treatment administration (Visit 18). [ Time Frame: During the study treatment until 14 days after the last CYAD-101 study treatment administration (Visit 18 = day 73). ]
    Dose-limiting toxicity refers to a specific adverse event that is experienced during treatment and until 2 weeks after last CYAD-101 dose administration, is new and at least possibly related to CYAD-101 study treatment.

  2. Expansion Segment: The objective response rate at Visit 18. [ Time Frame: on month 2,5 ]
    The objective response rate at Visit 18 (day 73)


Secondary Outcome Measures :
  1. Dose Escalation Segment and Expansion segment: CYAD-101 cell kinetics and dynamics endpoints [ Time Frame: from month 1 till month 2,5 ]

    This endpoint corresponds to the evaluation of the circulating CYAD-101 peripheral blood kinetics post-administration.

    CYAD-101 detection in peripheral blood-isolated PBMC will be mandatory performed until the end of the administration phase (Visit 18). If positive at Visit 18, the evaluation will be performed during the follow-up period visits and until 2 sequential tests are providing "undetectable" results, suggesting a lack of the CYAD-101 persistence.


  2. Dose Escalation Segment: Safety endpoints [ Time Frame: from month 1 till month 2,5 ]
    The occurrence of Adverse Events and Serious Adverse Events and Dose Limiting Toxicities during the study treatment until the administration phase concluding visit (Visit 18).

  3. Dose Escalation and Expansion Segment: Clinical activity endpoints (duration of response) [ Time Frame: up to month 2,4 ]
    The duration of response for patients with objective clinical response.

  4. Dose Escalation and Expansion Segment: Clinical activity endpoints (occurrence of mixed response) [ Time Frame: up to month 2,4 ]
    The occurrence of mixed response (MR) post CYAD-101 administration.

  5. Dose Escalation and Expansion Segment: Clinical activity endpoints (progression-free survival) [ Time Frame: up to month 2,4 ]
    The progression-free survival (PFS).

  6. Dose Escalation and Expansion Segment: Clinical activity endpoints (event-free survival) [ Time Frame: up to month 2,4 ]
    The event-free survival (EFS).

  7. Dose Escalation and Expansion Segment: Clinical activity endpoints (overall survival) [ Time Frame: up to month 2,4 ]
    The overall survival (OS).

  8. Expansion Segment: Safety endpoints (occurrence of Dose Limiting Toxicities) [ Time Frame: up to14 days after the last CYAD-101 study treatment administration (month 2,5) ]
    The occurrence of Dose Limiting Toxicities in all patients during the study treatment until 14 days after the last CYAD-101 study treatment administration (Visit 18).

  9. Expansion Segment: Safety endpoints (occurrence of Adverse Events, Serious Adverse Events and Dose Limiting Toxicities) [ Time Frame: up to 14 days after the last CYAD-101 study treatment administration (month 2,5). ]
    The occurrence of Adverse Events, Serious Adverse Events and Dose Limiting Toxicities during the study treatment until the administration phase concluding visit (Visit 18).

  10. Mandatory correlative study endpoints (characterization of systemic cytokine level release post CYAD-101) [ Time Frame: up to month 10 ]
    One of the key effector functions of CYAD-101 is the release of soluble cytokines during antigen engagement. Consequently, a surrogate marker of CYAD-101 in vivo activity is potentially raised levels of cytokines relevant to T cell activation within the peripheral circulation.

  11. Mandatory correlative study endpoints (evaluation of the NKG2D ligand expression within tumor samples prior to treatment administration) [ Time Frame: At screening ]
    The research will evaluate NKG2D ligand expression in patient tumor samples. These are likely to include tumor biopsies but also other sources such as circulating tumor cells where it is possible to isolate sufficient numbers for analysis. The aim of this section is to establish whether a correlation can be drawn between the level of tumor-based NKG2D ligand expression and CYAD-101 activity.

  12. Mandatory correlative study endpoints (evaluation of biological parameters documenting any Host versus Graft reaction) [ Time Frame: from month 1 up to month 10 ]
    Tumor cell death mediated by CYAD-101 may expose the immune system to new antigens, potentially boosting pre-existing tumor-related immunogenicities or inducing de novo anti-tumor immune responses. Evaluation and characterization of the study treatment mode of action, involving the characterization of the pre-existing and post/during-therapy immune response will be assessed. Moreover, the response of the donor against the allogeneic antigen present on the donor T cells may drive an immunological response clearing the CYAD-101 product. In part, the relative engraftment of CYAD-101 will provide some initial information concerning any potential HvG response (such as reduced persistence of the CYAD-101 cells after second and third infusion). Greater insight into any potential HvG response will be performed within this general immunological assessment of the consequence of CYAD-101 therapy.



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:

  1. The patient must have signed the written ICF and must accept to be monitored for up to 15 years in a Long-Term Safety Follow-Up (LTSFU) protocol.
  2. Both men and women of all races and ethnic groups are eligible.
  3. The patient must be < = 18 years old at the time of signing the ICF.
  4. The patient must have a histologically proven metastatic adenocarcinoma of the colon or rectum.

    • Unresectable metastases not treatable by surgical resection or local ablation with curative intent at time of study entry.
    • Unequivocal and measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1).
    • The patient is due to receive first-line metastatic chemotherapy regimen with FOLFOX, as permitted in this protocol.

    Notes: Patients who have received adjuvant chemotherapy or chemoradiotherapy to the pelvis, provided the last dose of chemotherapy was administered at least 6 months prior to the first CYAD-101 administration, are permitted.

  5. The patient must have an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
  6. The patient must have the bone marrow reserve, hepatic and renal functions described with LLN/ULN being the lower/upper limit of normal, respectively:

    • Hemoglobin > 9.0 g/dl
    • ANC > 800/µL
    • Platelet count >= 80000/µL
    • LDH <= 1.5 x ULN
    • Serum creatinine <= 2.0 mg/dl
    • Total serum bilirubin <= 1.75 mg/dL
    • ALT <= 5 x ULN
    • AST <= 5 x ULN
  7. The patient must agree to have a tumor biopsy at baseline. In specific cases, where tumor biopsy is not possible, decision to not perform the tumor biopsy may be taken by the Investigator but only after approval from the Sponsor.
  8. Ejection fraction of > 40%, as determined by echocardiography or a multigated acquisition (MUGA) scan.
  9. Women of child-bearing potential and men must agree to use effective contraception before, during and for at least 2 months after the last study treatment administration.

    Notes: Adequate contraception is defined as methods of birth control that, alone or in combination, result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly. These include established use of oral, injected or implanted hormonal methods of contraception; placement of an intrauterine device or intrauterine system; male sterilization, true abstinence (when this is in line with the preferred and usual lifestyle of the patient). Women of non-childbearing potential may be enrolled in the study. Non-childbearing potential is defined as the consequence of hysterectomy, ovariectomy or post-menopause.

  10. The patient must, in the opinion of the Investigator, be able to adhere with the study visit schedule and all study procedures described in this protocol.

Exclusion Criteria:

  1. The patient has a confirmed or suspected tumor metastasis in the central nervous system (CNS). A neurological examination is to be performed systematically at baseline. In case signs or symptoms suggestive of potential CNS disease are observed, CNS imaging is to be performed.

    Peripheral neuropathy from prior therapy is acceptable.

  2. Patients who have received any cancer therapy (investigational agent or not), including but not limited to chemotherapy, small molecules, monoclonal antibodies (e.g., immune checkpoint blockade therapies), or radiotherapy within 2 weeks before the planned D1.

    Note: Per study design the standard FOLFOX chemotherapy is authorized.

  3. Patients who are planned to receive or concurrently receiving any other non-cancer-directed investigational agent or have received another non-cancer-directed investigational agent within 3 weeks before the planned day for the first CYAD-101 administration.
  4. Patient is under systemic immunosuppressive drugs, unless specific cases authorized per protocol (see Section 6.5).
  5. Patients who have received prior allogeneic stem cell transplantation, chimeric antigen receptor therapy or other genetically modified T-cell therapy.
  6. Patients who are presenting persistent toxicities greater than or equal to CTCAE grade 2 caused by previous adjuvant cancer therapy (except for clinically non-significant toxicities, such as alopecia).
  7. Presence of any indwelling catheter or drain (e.g., percutaneous nephrostomy tube, indwelling foley catheter, biliary drain, or pleural/peritoneal/pericardial catheter) may be permissive unless they have a catheter-associated infection that cannot be cleared with antibiotics. Ommaya reservoirs and dedicated central venous access catheters such as a Port-a-Cath, peripherally inserted central catheter, or Hickman catheter are permitted.
  8. Patients who underwent major surgery within 4 weeks before the planned day for the first CYAD-101 administration.

    Note: Placement of vascular access device or tumor biopsies are authorized until 10 days before the planned day for the first CYAD-101 administration.

  9. Patients who have received a live vaccine within 6 weeks prior to the planned day for the first CYAD-101 administration.
  10. Patients with uncontrolled intercurrent illness or serious uncontrolled medical disorder including, but not limited to evidence of active pneumonitis on screening chest imaging, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia and/or pronounced disturbances of the electrical conduction system of the heart, or significant thromboembolic events.
  11. Patient with history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, and/or active or acute exacerbation of chronic obstructive pulmonary disease (COPD).

    Note: Patients with history or suspicion of COPD must have at least Forced Expiratory Volume in the first second (FEV-1)/ Forced Vital Capacity (FVC) >= 0,7 with FEV-1 >= 50% predicted (GOLD 1 or 2 severity).

  12. Patients who have active infections necessitating use of antibiotics/antivirals treatment (prophylaxis is acceptable).
  13. Patients with significant disorder of coagulation or receiving treatment with warfarin derivatives or heparin.

    Note: Patients receiving systemic individual doses of low molecular weight heparin outside 24 hours prior to each CYAD-101 administration are eligible.

  14. Patients who are known to be positive or screened positive for the human immunodeficiency virus (HIV).
  15. Patients with a family history of congenital or hereditary immunodeficiency.
  16. Patients with a history of allergic reactions or hypersensitivity attributed to Human serum albumin or Plasma-lyte A.
  17. Patients on supplemental home oxygen.
  18. Patients with history of any autoimmune disease including, but not limited to inflammatory bowel disease (including ulcerative colitis and Crohn's Disease), systemic progressive sclerosis (scleroderma), systemic lupus erythematosus, autoimmune vasculitis (e.g., Wegener's granulomatosis), CNS or motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre syndrome and myasthenia gravis, multiple sclerosis). Patients with Graves disease and vitiligo will be allowed.
  19. Patients with a history of a malignancy other than the one evaluated in this study enrollment, with exception of the following circumstances:

    • Patients with a history of malignancy who have been adequately treated and have been disease-free for at least 1 year, and
    • Patients with adequately treated active non-invasive cancers (such as non-melanomatous skin cancer or in-situ bladder, cervical and breast cancers).
  20. Patients with psychiatric/social situations or addictive disorders that may compromise the ability of the patients to give informed consent or to comply with the study procedures
  21. Female patients who are pregnant or lactating.

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): NCT03692429


Contacts
Layout table for location contacts
Contact: Florence Renard 0032 (0)10 39 41 01 ext 101 frenard@Celyad.com
Contact: Anne Flament 0032 (0)10 39 42 38 aflament@celyad.com

Locations
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Belgium
Institut Jules Bordet Not yet recruiting
Brussels, Belgium, 1000
Contact: Michel Dubuisson         
Principal Investigator: Leila Shaza, MD         
UZ Antwerpen Recruiting
Edegem, Belgium, 2650
Contact: Hans Prenen, MD         
Principal Investigator: Hans Prenen, MD         
UZ Leuven Active, not recruiting
Leuven, Belgium, 3000
United Kingdom
Guy's and St Thomas' NHS Foundation Trust Not yet recruiting
London, United Kingdom, SE1 9RT
Contact: Sophie Papa, MD         
Principal Investigator: Sophie Papa, MD         
The Christie NHS Foundation Trust Not yet recruiting
Manchester, United Kingdom, M20 4BX
Contact: Fiona Thistlethwaite, MD         
Principal Investigator: Fiona Thistlethwaite, MD         
Sponsors and Collaborators
Celyad (formerly named Cardio3 BioSciences)
Novella Clinical

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Responsible Party: Celyad (formerly named Cardio3 BioSciences)
ClinicalTrials.gov Identifier: NCT03692429     History of Changes
Other Study ID Numbers: CYAD-N2L-101
First Posted: October 2, 2018    Key Record Dates
Last Update Posted: December 3, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Celyad (formerly named Cardio3 BioSciences):
unresectable metastatic colorectal cancer

Additional relevant MeSH terms:
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Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Oxaliplatin
Fluorouracil
Antineoplastic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs