Preoperative immunotherapy with atezolizumab (Tecentriq®) and tiragolumab or atezolizumab (Tecentriq®) and bevacizumab (Avastin®) in patients with colorectal liver metastases (CRLM) (the PURPLE trial)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitaetsklinikum Essen AöR

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

16 Dec 2024 → ongoing

Decision date (initial)

2024-08-15

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

The primary objective of this study is to estimate the pathological tumor response rate (Tumor regression grade (TRG) 1 and 2 according to Rubbia Brandt) on routine hematoxylin and eosin staining of resected tumors.

Secondary objectives 6

1. To assess the feasibility of the study design, defined as > 80% of patients (10 out of 12 in the experimental arms) who underwent surgery
2. To evaluate safety of preoperative short time immunotherapy and assessment of postoperative complication rates within 90 days of surgery
3. To assess resectability in patients with or without preoperative immunotherapy
4. To determine PET response in patients with or without preoperative short term IO therapy
5. To identify reasons for no surgery
6. To estimate pathological response rate according to Rubbia Brandt by independent central review

Conditions and MedDRA coding

Colorectal liver metastases (CRLM)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Male or female, 18 years of age or older on day of signing informed consent form
2. Patient is willing and able to comply with the protocl for the duration of the study including undergoing treatment and scheduled visits and examinations
3. Signed informed consent
4. Histologically confirmed adenocarcinoma [mixed adenoneuroendocrine (MANEC) are alowed, if predominant part in adenocarcinoma] of the colon or rectum with liver metastases (CRLM)(synchronous or metachronous) that are amenable to surgical resection with curative intent based on the decision of the local multidisciplinary tumor board. Two stages resections of CRLM and primary tumor is allowed according to local guidelines.
5. CRLM have to be accessible for biopsy
6. Microsatellite stable (MSS)/proficient mismatch repair (pMMR) disease (assessed from biopsy of from resected tumor tissue)
7. No evidence of disease (NED) outside of the liver and the primary tumor, with the exception of local lymph node metastases. If primary tumor is in situ, it must be resectable.
8. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1
9. Adequate hematologic, hepatic and renal function, defined by the following laboratory test results, obtained within 14 days prior to initiation of study treatment: - Absolute neutrophil count (ANC) ≥ 1.5 × 109/L without granulocyte colony-stimulating factor support; - Lymphocyte count ≥0.5 x 109/L; - Platelet count ≥100 x 109/L without transfusion; - Hemoglobin ≥90 g/L o Patients may be transfused to meet this criterion but patients in need of chronic or repeated red blood cell (RBC) transfusion should be discussed with the Global Lead before; - Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and Alkaline Phosphatase (ALP) ≤ 2.5 x upper limit of normal (ULN); - Total bilirubin ≤ 1.5 x ULN with the following exception: o Patients with known Gilbert disease: total bilirubin level ≤3 x ULN; - Serum creatinine ≤1.5 x ULN or Creatinine clearance ≥ 45 mL/min (calculated using the Cockcroft-Gault formula); - Serum albumin ≥2.5 g/dL; - International normalized ratio (INR) and activated Partial Thromboplastin Time (aPTT) ≤1.5 x ULN [This applies only to patients who do not receive therapeutic anticoagulation; patients receiving therapeutic anticoagulation (such as low−molecular weight heparin or warfarin) should be on a stable dose]
10. Negative human immunodeficiency virus (HIV) test at screening (see exclusion criterion 16 for exceptions)
11. For patients with hepatitis B virus (HBV): HBV DNA < 500 IU/mL (or 2,500 copies/mL) at screening Patients with detectable hepatitis B surface antigen (HBsAg) or detectable HBV DNA should be managed per institutional treatment guidelines. Patients receiving anti-viral medication must have initiated treatment for at least 2 weeks prior to randomization and should continue treatment for at least 6 months after the final dose of study treatment
12. Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening The HCV RNA test will be performed only for patients who have a positive HCV antibody test.
13. For women of childbearing potential (WCBP): A woman is considered to be of childbearing potential if she is post-menarchal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). • Should have a negative serum pregnancy test within 14 days prior to randomization. • Agreement to remain abstinent (refrain from heterosexual intercourse) or use a contraceptive method with a failure rate of <1% per year during the treatment period and for at least 5 months after last study drug administration. • Examples of contraceptive methods with a failure rate of <1% per year include bilateral tubal ligation, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices and copper intrauterine devices. • The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception
14. For men: Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating sperm, as defined below: • Men with a female partner of childbearing potential or pregnant female partner: men must be sterilized or remain abstinent or use a condom during the treatment period and for 90 days after the last dose of tiragolumab or atezolizumab to avoid exposing the embryo. • The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence and withdrawal are not acceptable methods of contraception. • Men must refrain from donating sperm during this same period.

Exclusion criteria 49

1. Evidence of metastases, except for liver and local lymph node metastases
2. Anti-hypertensive therapy to achieve these parameters is allowed.
3. History of hypertensive crisis or hypertensive encephalopathy
4. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to initiation of study treatment
5. History of hemoptysis (>2.5 mL of bright red blood per episode) within 1 month prior to initiation of study treatment
6. Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)
7. Current or recent (< 10 days prior to initiation of study treatment) use of aspirin (>325 mg/day) or clopidogrel (> 75 mg/day)
8. Use of full-dose oral or parenteral anticoagulants for therapeutic purpose is permitted as long as the INR and/or aPTT is within therapeutic limits (according to institution standards) within 7 days prior to initiation of study treatment and the patient has been on a stable dose of anticoagulants for > 2 weeks prior to initiation of study treatment. Prophylactic use of anticoagulants is allowed.
9. Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture
10. Grade ≥ 2 proteinuria, as demonstrated by ≥2+ protein on dipstick urinalysis and ≥1.0 g of protein in a 24-hour urine collection. All patients with ≥ 2+ protein on dipstick urinalysis at screening must undergo a 24-hour urine collection for protein. Patients with < 2+ protein on dipstick urinalysis are eligible for the study.
11. Haemorrhagic diathesis or known thrombophilia
12. Prior treatment with immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, anti-PD-L1 and anti-TIGIT therapeutic antibodies
13. The history or presence of gastrointestinal perforation, intra-abdominal abscess, active severe peptic ulcer disease, or recent intra-abdominal inflammatory conditions (e.g., diverticulitis, colitis)
14. Concomitant use of herbal therapies for treatment of cancer
15. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
16. Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab, tiragolumab or bevacizumab formulation
17. Uncontrolled hypercalcemia (> 1.5 mmol/L ionized calcium or Ca > 12 mg/dL or corrected serum calcium > ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab
18. Uncontrolled tumor-related pain. Patients requiring narcotic pain medication must be on a stable regimen at study entry Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) amenable to palliative radiotherapy should be treated prior to enrollment. Patients should be recovered from the effects of radiation. There is no required minimum recovery period. Asymptomatic metastatic lesions that would likely cause functional deficits or intractable pain with further growth (e.g., epidural metastasis that is not currently associated with spinal cord compression) should be considered for loco-regional therapy if appropriate prior to enrollment.
19. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently). Patients with indwelling catheters (e.g., PleurX) are allowed.
20. Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL or corrected serum calcium > ULN)
21. Presence of severe infection within 4 weeks prior to to randomization, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia, or any active infection that, in the opinion of the investigator, could impact patient safety
22. Positive human immunodeficiency virus (HIV) Known HIV+ patients may be included but must have: a. A stable regimen of highly active anti-retroviral therapy (HAART) for at least 3 months b. No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections c. A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard PCR-based tests
23. Treatment with investigational therapy within 4 weeks prior to randomization
24. Active hepatitis B virus (HBV) infection (chronic or acute), defined as having a positive hepatitis B surface antigen (HBsAg) test at screening
25. Patients with a past or resolved HBV infection, defined as having a negative HBsAg test and a positive total hepatitis B core antibody (HBcAb) test at screening followed by a negative HBV DNA test, are eligible for the study. The HBV DNA test will be performed only for patients who have a positive total HBcAb test.
26. Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test followed by a positive HCV ribonucleic acid (RNA) test at screening. The HCV RNA test will be performed only for patients who have a positive HCV antibody test
27. Active tuberculosis
28. Treatment with therapeutic oral or i.v. antibiotics within 2 weeks prior to randomization Exception: Prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation
29. Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, anti-phospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis (see Appendix I for a more comprehensive list of autoimmune diseases and immune deficiencies) with the following exceptions: - Patients with a history of autoimmune-related hypothyroidism who are on thyroid replacement hormone are eligible for the study - Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study - Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., no psoriatic arthritis) may be eligible provided that they meet the following conditions: a. Rash covering less than 10% of the body surface area. b. Controlled disease at baseline requiring only low potency topical steroids. c. No acute exacerbations of underlying condition within the last 12 months (e.g. not requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, high potency, or oral steroids).
30. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computer tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
31. Side effects of any previous radiotherapy, chemotherapy, targeted therapy or surgical procedure that have not resolved to Grade ≤1, except alopecia (any grade) and Grade 2 neuropathy
32. Prior allogeneic stem cell or solid organ transplantation
33. Active malignancy or history of malignancy within the past 3 years. Exceptions: Completely resected basal cell carcinoma, cutaneous squamous cell carcinoma, cervical carcinoma in-situ, breast carcinoma in-situ, and isolated elevation in prostate-specific antigen in the absence of radiographic evidence of metastatic prostate cancer
34. Any anti-cancer therapy, including chemotherapy or hormonal therapy or radiotherapy, within 2 weeks prior to randomization
35. Any Grade ≥ 3 hemorrhage within 4 weeks prior to randomization Exception: Grade ≥ 3 hemorrhage during resection of primary tumor is allowed.
36. History of stroke, reversible ischemic neurological defect, or transient ischemic attack within 6 months prior to randomization
37. Significant cardiovascular disease, such as New York Heart Association (NYHA) cardiac disease (Class II or greater), myocardial infarction within 6 months prior randomization, severe cardiac arrhythmia requiring medication or severe conduction abnormalities, unstable arrhythmias, acute coronary syndromes (including unstable angina), known left ventricular ejection fraction (LVEF) <40% or history of coronary angioplasty/stenting/bypass grafting within past 6 months. Exceptions: Patients with known coronary artery disease, or congestive heart failure not meeting the above criteria, being on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist, if appropriate
38. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug according to the investigator’s brochure (IB)
39. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that may affect the interpretation of the results, or may render the patient at high risk from treatment complications in the opinion of the investigator
40. Criteria which in the opinion of the investigator preclude participation for scientific reasons, for reasons of compliance, or for reasons of the patient’s safety
41. Participation in another clinical study within the last 3 months prior to inclusion with the exception of studies evaluating radiological imaging, surgical studies and non-interventional studies
42. Simultaneous participation in other clinical studies with the exception of studies evaluating radiological imaging and non-interventional studies
43. Pregnant or lactating women or intention of becoming pregnant during study treatment, within 5 months after the final dose of study treatment
44. Major surgical procedure other than for diagnosis within 4 weeks prior to randomization Exception: Surgery of primary tumor within 2 weeks prior to randomization is allowed.
45. Treatment with systemic immunosuppressive medications (including, but not limited to, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) within 2 weeks prior to randomization. Note: The use of inhaled corticosteroids, physiologic replacement doses of glucocorticoids (i.e. for adrenal insufficiency) and mineralocorticoids (e.g. fludrocortisone) is allowed
46. Treatment with a live-attenuated vaccine within 4 weeks prior to randomization, or anticipation of need for such a vaccine during study treatment, within 90 days after the final dose of tiragolumab, or within 5 months after the final dose of atezolizumab.
47. Treatment with systemic immuno-stimulatory agents (including, but not limited to, interferon and interleukin 2 [IL-2]) within 4 weeks or five half-lives of the drug (whichever is longer) prior to randomization
48. Inadequately controlled hypertension, defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg (average of at least three readings at two or more sessions)
49. Legal incapacity or limited legal capacity

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Percentage of resected patients with complete or major pathological regression

Secondary endpoints 8

1. Percentage of patients who underwent surgery after preoperative IO therapy
2. Incidence, relatedness and severity of adverse events occurring during preoperative short time immunotherapy within 90 days of surgery (Severity for all events will be graded according to NCI CTCAE v5.0)
3. Assessment of postoperative complication rates according to the Clavien-Dindo Classification
4. Mortality within 90 days of surgery
5. Estimation of curative (R0) resection rate
6. Assessment of PET response (PET-CT or PET-MRI) after short term immunotherapy
7. Patients, who do not undergo surgery: Reasons for not having surgery
8. Percentage of resected patients with complete or major pathological regression as evaluated by independent central review

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitaetsklinikum Essen AöR

Sponsor organisation

Universitaetsklinikum Essen AöR

Address

Hufelandstrasse 55, Holsterhausen Holsterhausen

City

Essen

Postcode

45147

Country

Germany

Scientific contact point

Organisation

Universitaetsklinikum Essen AöR

Contact name

Prof. Stefan Kasper-Virchow

Public contact point

Organisation

Universitaetsklinikum Essen AöR

Contact name

Studienzentrum GmbH

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 1 · Art. 38 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 7 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications