Combined PD-1 and CCR5 Inhibition for the Treatment of Refractory Microsatellite Stable mCRC

NCT03274804 | Completed Phase 1 Results DMC

• 1 other identifier: PICCASSO
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

This is a monocentric, single arm, prospective, open-label trial of a combination treatment consisting of pembrolizumab and maraviroc in previously treated subjects who have refractory microsatellite stable (MSS) metastatic colorectal cancer (mCRC).

Conditions

Metastatic Colorectal Cancer; MSS

Outcome Measures

Primary Outcomes (1)

• Feasibility Rate of a Combined Therapy

  Defined as the rate of patients receiving the protocol treatment according to the planned schedule without occurrence of at least one of the following events: Study treatment-related Grade ≥ 3 immune-related abnormalities; Study treatment-related Grade ≥ 4 AEs of any aetiology; Any toxic event leading to the premature withdrawal of protocol treatment

  After core treatment period of 8 cycles (each cycle is 21 days)

Secondary Outcomes (5)

• Safety and Toxicity of a Combined Therapy Based on Subjects Who Experienced Toxicities

  After core treatment period of 8 cycles (each cycle is 21 days)

• Efficacy Endpoint: Disease Control Rate

  through study completion (20 months)

• Efficacy Endpoint: Objective Response Rate

  through study completion (20 months)

• Efficacy Endpoint: Progression-free Survival

  through study completion (20 months)

• Overall Survival

  through study completion (20 months)

Study Arms (1)

Single arm, prospective, open-label trial

EXPERIMENTAL

Eligible subjects will receive pembrolizumab beginning on Day 1 of each 3-week dosing cycle (d1, qd22) together with maraviroc administered perorally on day 1 to 21 of each cycle (d1-21; qd22).

Biological: Pembrolizumab; Drug: Maraviroc

Interventions

Pembrolizumab BIOLOGICAL

Eligible subjects will receive pembrolizumab beginning on Day 1 of each 3-week dosing cycle (d1, qd22)

Also known as: Keytruda

Single arm, prospective, open-label trial

Maraviroc DRUG

Maraviroc will be administered perorally on day 1 to 21 of each cycle (d1-21; qd22)

Also known as: Celsentri

Single arm, prospective, open-label trial

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically confirmed metastatic colorectal cancer. Microsatellite stability (MSS) is confirmed by PCR or immunohistochemistry.
• Patient failed standard therapy or is intolerable towards standard therapy which must include a fluoropyrimidine, oxaliplatin, irinotecan, an antiangiogenic monoclonal antibody (e.g. bevacizumab, aflibercept, ramucirumab), an EGFR inhibitor in case of RAS/BRAF wildtype tumors and optional regorafenib or TAS 102
• Measurable disease as per RECIST 1.1
• Metastatic lesion accessible for repetitive biopsies and patient willing to provide tissue from newly obtained biopsies. Patients without accessible lesions might be enrolled after discussion with the principle investigator.
• ECOG performance status 0 or 1
• Adequate hematological, hepatic and renal function parameters:
• Leucocytes\> 3.000/μl
• Hemoglobin \>9 g/dl
• Thrombocytes \> 100.000/μl
• Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or GFR ≥60 mL/min for subject with creatinine levels \> 1.5 x institutional ULN
• Serum total bilirubin ≤ 1.5 x upper limit of normal or direct bilirubin ≤ ULN for subjects with total bilirubin levels \> 1.5 ULN
• AST and ALT ≤ 2.5 x upper limit of normal (or ≤ 5 x if liver metastases are present)
• Albumin ≥ 2.5 mg/dL
• Adequate coagulation functions as defined by International Normalized Ratio (INR) ≤1.5, and a partial thromboplastin time (PTT) ≤ 5 seconds above the ULN (unless receiving anticoagulation therapy). Patients receiving warfarin/ phenprocoumon must be switched to low molecular weight heparin and have achieved stable coagulation profile.
• Female and male patients' ≥ 18 years. Patients in reproductive age must be willing to use adequate contraception during the study and 4 months after the end of the study (appropriate contraception is defined as surgical sterilization (e.g., bilateral tubal ligation, vasectomy), hormonal contraception (implantable, patch, oral), and doublebarrier methods (any double combination of: IUD, male or female condom with spermicidal gel, diaphragm, sponge, cervical cap)). Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if it is consistently employed as the subject's preferred and usual lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable methods of contraception. Female patients with childbearing potential need to have a negative pregnancy test within 7 days before study start.

You may not qualify if:

• Inability to understand the aims of the study and/or protocol procedures
• Hypersensitivity towards pembrolizumab, maraviroc, or any ingredients of the formulations administered
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies
• Any other concurrent antineoplastic treatment including irradiation (local radiation of single non-target lesions for palliation only allowed)
• Active autoimmune disease requiring immunosuppressive therapy
• Any condition requiring continuous systemic treatment with either corticosteroids (\>10 mg daily prednisone equivalents) or other immunosuppressive medications within 2 weeks prior to first dose of study treatment. Inhaled or topical steroids and physiological replacement doses of up to 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease.
• Secondary malignant disease during the last 5 years (exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy).
• Clinical relevant comorbidity also including significant psychiatric disease
• Clinically significant active coronary heart disease, cardiomyopathy or congestive heart failure, NYHA III-IV
• Cardiocirculatory insufficiency with hypotension (systolic blood pressure \<100 mmHg)
• Cirrhosis of the liver (Child \> Grade A), pronounced alcohol abuse with anticipated detoxification, severe pulmonary infection with considerable reduction of pulmonary function
• Prior allogeneic bone marrow transplantation
• Prior treatment with anti-PD-1, anti-PD-L1, or anti-PD-L2 therapeutic antibody
• Administration of a live, attenuated vaccine within four weeks prior to start of maintenance treatment or anticipation that such a live attenuated vaccine will be required during the remainder of the study 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.
• Chronic intake of drugs that lead to known interference with Maraviroc metabolism through strong Cytochrome P450 3A4 (CYP3A4) interaction: e.g. Rifampicin, Rifabutin, Clarithromycin, Telithromycin, Ketoconazole, Itraconazole, Fluconazole, Hypericum perforatum (St. John's Worth /Johanniskraut) or any strong CYP3A4 inducing or inhibiting drug (See Section 5.5.2)

Sponsors & Collaborators

• University Hospital Heidelberg: lead
• Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest: collaborator

Study Sites (1)

National Center for Tumor Diseases, University Hospital Heidelberg

Heidelberg, Germany

Location

Related Publications (1)

• Haag GM, Springfeld C, Grun B, Apostolidis L, Zschabitz S, Dietrich M, Berger AK, Weber TF, Zoernig I, Schaaf M, Waberer L, Muller DW, Al-Batran SE, Halama N, Jaeger D. Pembrolizumab and maraviroc in refractory mismatch repair proficient/microsatellite-stable metastatic colorectal cancer - The PICCASSO phase I trial. Eur J Cancer. 2022 May;167:112-122. doi: 10.1016/j.ejca.2022.03.017. Epub 2022 Apr 12.

  PMID: 35427833 DERIVED

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

pembrolizumab; Maraviroc

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Dr. Georg Martin Haag
• Organization: Universitätsklinikum Heidelberg, NCT

GeorgMartin.Haag@med.uni-heidelberg.de

+49 (0) 6221 56

Study Officials

• Dirk Jäger, Prof.

  NCT, Med Oncology, University Hospital Heidelberg

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr.

Study Record Dates

• First Submitted: August 14, 2017
• First Posted: September 7, 2017
• Study Start: April 1, 2018
• Primary Completion: March 1, 2020
• Study Completion: March 1, 2020
• Last Updated: June 7, 2022
• Results First Posted: April 22, 2021

Record last verified: 2022-05

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1)