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

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).

Treatment with pembrolizumab / maraviroc combination will continue until progressive disease (PD), unacceptable adverse events (AEs), intercurrent illness that prevents further administration of treatment, investigator's decision to withdraw the subject, subject withdraws consent, pregnancy of the subject, noncompliance with trial treatment or procedure requirements, administrative reasons requiring cessation of treatment, or completion of treatment per protocol.

Subjects with a treatment response or stable disease after completion of the first treatment phase of eight cycles (core treatment period) will be offered, at the discretion of the investigator, participation in a maintenance phase consisting of up to 24 additional treatment cycles of pembrolizumab monotherapy (total treatment duration up to 24 months).

Subjects who discontinue for reasons other than PD will have post-treatment follow-up for disease status until PD, initiating a non-study cancer treatment, withdrawing consent, or becoming lost to follow-up. All subjects will be followed for overall survival (OS) until death, withdrawal of consent, loss to follow-up, or the end of the study.

After the end of treatment, each subject will be followed for 30 days for AE monitoring. Serious adverse events (SAEs) and AEs of special interest (AESIs) will be collected for 90 days after the end of treatment or for 30 days after the end of treatment if the subject initiates new anticancer therapy, whichever is earlier.

• Pembrolizumab (Biological), also known as Keytruda: Eligible subjects will receive pembrolizumab beginning on Day 1 of each 3-week dosing cycle (d1, qd22)
• Maraviroc (Drug), also known as Celsentri: Maraviroc will be administered perorally on day 1 to 21 of each cycle (d1-21; qd22)

Primary outcomes

• Feasibility Rate of a Combined Therapy [After core treatment period of 8 cycles (each cycle is 21 days)]: 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

Secondary outcomes

• 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)]: The primary safety analysis will be based on subjects who experienced toxicities as defined by the current National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE, v4.0; Section 11.2). The attribution to drug, time-of-onset, duration of the event, its resolution, and any concomitant medications administered will be recorded.
• Efficacy Endpoint: Disease Control Rate [through study completion (20 months)]: Determine DCR defined as percentage of patients displaying CR/PR or SD as best response according to the RECIST criteria version 1.1.
• Efficacy Endpoint: Objective Response Rate [through study completion (20 months)]: ORR and immune related (ir) ORR (irORR) will be analyzed.
• Efficacy Endpoint: Progression-free Survival [through study completion (20 months)]: Individual PFS will be analyzed.
• Overall Survival [through study completion (20 months)]: Individual OS will be analyzed.

Sex: All, ages: 18 Years to any

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.

Participant flow

Outcome results

• Feasibility Rate of a Combined Therapy (Primary), Count of participants, Participants: Single Arm, Prospective, Open-label Trial 18
• Safety and Toxicity of a Combined Therapy Based on Subjects Who Experienced Toxicities (Secondary), Count of participants, Participants: Study Treatment Arm 20
• Efficacy Endpoint: Disease Control Rate (Secondary), Count of participants, Participants: Study Treatment Arm 1
• Efficacy Endpoint: Objective Response Rate (Secondary), Count of participants, Participants: Single Arm, Prospective, Open-label Trial 1
• Efficacy Endpoint: Progression-free Survival (Secondary), Median, weeks: Study Treatment Arm 9 (7.00 to 10.00)
• Overall Survival (Secondary), Median, Time until event, month: Study Treatment Arm 9 (6.00 to 20.00)

Adverse events

Time frame: From the time of treatment allocation through 30 days following discontinuation of treatment, up to 20 months, all adverse events must be reported by the investigator.

Serious adverse events by term

Other adverse events by term

22 more terms not shown.

• Results publication: 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

• Study Protocol and Statistical Analysis Plan (PDF, 2018-08-01)

• Dirk Jäger, Prof., Principal investigator, NCT, Med Oncology, University Hospital Heidelberg