Combined PD-1 and CCR5 Inhibition for the Treatment of Refractory Microsatellite Stable mCRC
Condition: Metastatic Colorectal Cancer; MSS
MeSH terms: Colorectal Neoplasms
Intervention: Pembrolizumab; Maraviroc
Intervention description: Eligible subjects will receive pembrolizumab beginning on Day 1 of each 3-week dosing cycle (d1, qd22); Maraviroc will be administered perorally on day 1 to 21 of each cycle (d1-21; qd22)
Intervention MeSH terms: Maraviroc; Pembrolizumab
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 20.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

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).
    

Eligibility criteria:

        Inclusion Criteria:

          1. Histologically confirmed metastatic colorectal cancer. Microsatellite stability (MSS)
             is confirmed by PCR or immunohistochemistry.

          2. 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

          3. Measurable disease as per RECIST 1.1

          4. 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.

          5. ECOG performance status 0 or 1

          6. 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

          7. 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.

          8. 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.

          9. Patient able and willing to provide written informed consent and to comply with the
             study protocol and with the planned surgical procedures.

        Exclusion Criteria:

          1. Inability to understand the aims of the study and/or protocol procedures

          2. Hypersensitivity towards pembrolizumab, maraviroc, or any ingredients of the
             formulations administered

          3. History of severe allergic, anaphylactic, or other hypersensitivity reactions to
             chimeric or humanized antibodies

          4. Any other concurrent antineoplastic treatment including irradiation (local radiation
             of single non-target lesions for palliation only allowed)

          5. Active autoimmune disease requiring immunosuppressive therapy

          6. 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.

          7. 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).

          8. Clinical relevant comorbidity also including significant psychiatric disease

          9. Clinically significant active coronary heart disease, cardiomyopathy or congestive
             heart failure, NYHA III-IV

         10. Cardiocirculatory insufficiency with hypotension (systolic blood pressure <100 mmHg)

         11. Cirrhosis of the liver (Child > Grade A), pronounced alcohol abuse with anticipated
             detoxification, severe pulmonary infection with considerable reduction of pulmonary
             function

         12. Prior allogeneic bone marrow transplantation

         13. Prior treatment with anti-PD-1, anti-PD-L1, or anti-PD-L2 therapeutic antibody

         14. 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.

         15. 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)

         16. Positive test for human immunodeficiency virus (HIV) or HIV infection

         17. Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg]
             test) or hepatitis C. Note: Patients with past hepatitis B virus (HBV) infection or
             resolved HBV infection (defined as having a negative HBsAg test and a positive
             antibody to hepatitis B core antigen antibody test) are eligible.

         18. Active or latent tuberculosis

         19. Clinically active brain metastases, defined as untreated symptomatic, or requiring
             therapy with steroids or anticonvulsants to control associated symptoms.

             Subjects with treated brain metastases that are no longer symptomatic and require no
             treatment with steroids may be included in the study if they have recovered from the
             acute toxic effect of radiotherapy and have no evidence of disease progression on
             imaging studies (MRI/CT scan).

         20. On-treatment participation in another clinical study in the period 30 days prior to
             start of study treatment and during the study

         21. Patients in a closed institution according to an authority or court decision (AMG §
             40, Abs. 1 No. 4)

         22. Pregnancy or lactation

         23. Known history of, or any evidence of active, non-infectious pneumonitis or
             interstitial lung disease.

         24. Active infection requiring systemic therapy.