Metastatic Colorectal Cancer, MSS
Conditions
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).
Detailed description
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.
Interventions
BIOLOGICALPembrolizumab
Eligible subjects will receive pembrolizumab beginning on Day 1 of each 3-week dosing cycle (d1, qd22)
DRUGMaraviroc
Maraviroc will be administered perorally on day 1 to 21 of each cycle (d1-21; qd22)
Sponsors
Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
University Hospital Heidelberg
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Study Treatment Arm All enrolled subjects received pembrolizumab 200 mg IV on day one every three weeks (d1, qd22; Q3W) plus maraviroc 2 x 300 mg p.o. daily as combination therapy in an unblinded fashion. | 20 |
| Total | 20 |
Baseline characteristics
| Characteristic | Study Treatment Arm |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 9 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants |
| Age, Continuous | 61 years STANDARD_DEVIATION 8.94 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 19 Participants |
| Region of Enrollment Germany | 20 Participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 20 |
| other Total, other adverse events | 20 / 20 |
| serious Total, serious adverse events | 4 / 20 |
Outcome results
Primary
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
Time frame: After core treatment period of 8 cycles (each cycle is 21 days)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Single Arm, Prospective, Open-label Trial | Feasibility Rate of a Combined Therapy | 18 Participants |
Secondary
Efficacy Endpoint: Disease Control Rate
Determine DCR defined as percentage of patients displaying CR/PR or SD as best response according to the RECIST criteria version 1.1.
Time frame: through study completion (20 months)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Single Arm, Prospective, Open-label Trial | Efficacy Endpoint: Disease Control Rate | 1 Participants |
Secondary
Efficacy Endpoint: Objective Response Rate
ORR and immune related (ir) ORR (irORR) will be analyzed.
Time frame: through study completion (20 months)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Single Arm, Prospective, Open-label Trial | Efficacy Endpoint: Objective Response Rate | 1 Participants |
Secondary
Efficacy Endpoint: Progression-free Survival
Individual PFS will be analyzed.
Time frame: through study completion (20 months)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Single Arm, Prospective, Open-label Trial | Efficacy Endpoint: Progression-free Survival | 9 weeks |
Secondary
Overall Survival
Individual OS will be analyzed.
Time frame: through study completion (20 months)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Single Arm, Prospective, Open-label Trial | Overall Survival | 9 Time until event, month |
Secondary
Safety and Toxicity of a Combined Therapy Based on Subjects Who Experienced Toxicities
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.
Time frame: After core treatment period of 8 cycles (each cycle is 21 days)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Single Arm, Prospective, Open-label Trial | Safety and Toxicity of a Combined Therapy Based on Subjects Who Experienced Toxicities | 20 Participants |