Clinical Trials /

NIVOLUMAB Plus IPILIMUMAB and TEMOZOLOMIDE in Microsatellite Stable, MGMT Silenced Metastatic Colorectal Cancer

NCT03832621

Description:

This is a Phase II, multicenter, single-arm trial designed to evaluate the efficacy and safety of nivolumab (NIVO), ipilimumab (IPI) and temozolomide (TMZ) combination in 27 patients with MSS, MGMT-silenced mCRC with initial clinical benefit following lead-in treatment with single-agent TMZ. Immune checkpoint inhibitors have been shown to trigger durable antitumor effects in a subset of patients. A high number of tumor mutations (so called 'tumor mutational burden') has recently been found associated with increased immunogenicity (due to a high number of neoantigens) and improved treatment efficacy across several different solid tumors. In mCRCs, only a small fraction of tumors (<5%) display a high mutational load and are usually associated with inactivation of mismatch repair genes such as MLH1, MSH2 and MSH6. Checkpoint inhibitors may have increased activity in dMMR/microsatellite instability-high (MSI-H) tumors, a hypothesis which was tested in various Phase II trials with positive results. On the opposite, mismatch repair proficient colorectal cancer is unresponsive to immune checkpoint inhibitors. Previous reports indicate that acquired resistance to TMZ may emerge through the induction of a microsatellite-instability-positive phenotype and recent data showed that inactivation of MMR, driven by acquired resistance to the clinical agent temozolomide, increased mutational load, promoted continuous renewal of neoantigens in human colorectal cancers and triggered immune surveillance in mouse models. On all of the above grounds, the investigators hypothesize that treatment of microsatellite stable MGMT hypermethylated CRCs with alkylating agents could reshape the tumor genetic landscape by increasing the tumor mutational burden, leading to achieve potential sensitization to immunotherapy.

Related Conditions:
  • Colorectal Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: NIVOLUMAB Plus IPILIMUMAB and TEMOZOLOMIDE in Microsatellite Stable, MGMT Silenced Metastatic Colorectal Cancer
  • Official Title: NIVOLUMAB Plus IPILIMUMAB and TEMOZOLOMIDE in Combination in Microsatellite Stable (MSS), MGMT Silenced Metastatic Colorectal Cancer (mCRC): the MAYA Study

Clinical Trial IDs

  • ORG STUDY ID: INT202-18
  • NCT ID: NCT03832621

Conditions

  • Metastatic Colorectal Cancer

Interventions

DrugSynonymsArms
Temozolomidetemozolomide + nivolumab + ipilimumab
Nivolumabtemozolomide + nivolumab + ipilimumab
Ipilimumabtemozolomide + nivolumab + ipilimumab

Purpose

This is a Phase II, multicenter, single-arm trial designed to evaluate the efficacy and safety of nivolumab (NIVO), ipilimumab (IPI) and temozolomide (TMZ) combination in 27 patients with MSS, MGMT-silenced mCRC with initial clinical benefit following lead-in treatment with single-agent TMZ. Immune checkpoint inhibitors have been shown to trigger durable antitumor effects in a subset of patients. A high number of tumor mutations (so called 'tumor mutational burden') has recently been found associated with increased immunogenicity (due to a high number of neoantigens) and improved treatment efficacy across several different solid tumors. In mCRCs, only a small fraction of tumors (<5%) display a high mutational load and are usually associated with inactivation of mismatch repair genes such as MLH1, MSH2 and MSH6. Checkpoint inhibitors may have increased activity in dMMR/microsatellite instability-high (MSI-H) tumors, a hypothesis which was tested in various Phase II trials with positive results. On the opposite, mismatch repair proficient colorectal cancer is unresponsive to immune checkpoint inhibitors. Previous reports indicate that acquired resistance to TMZ may emerge through the induction of a microsatellite-instability-positive phenotype and recent data showed that inactivation of MMR, driven by acquired resistance to the clinical agent temozolomide, increased mutational load, promoted continuous renewal of neoantigens in human colorectal cancers and triggered immune surveillance in mouse models. On all of the above grounds, the investigators hypothesize that treatment of microsatellite stable MGMT hypermethylated CRCs with alkylating agents could reshape the tumor genetic landscape by increasing the tumor mutational burden, leading to achieve potential sensitization to immunotherapy.

Detailed Description

      In advanced CRC, the occurrence of chemorefractory disease poses a major therapeutic
      challenge for presence of an adequate performance status to potentially receive further
      treatments. Patients who progress after all approved treatments may be generally considered
      suitable for new investigational drugs or strategies. Thus, in the era of personalized
      medicine, tumor molecular profiling may lead to the identification of therapeutic targets or
      predictive biomarkers for pharmacological intervention. The DNA repair gene
      O6-methylguanine-DNA methyltransferase (MGMT) is responsible of the elimination of alkyl
      groups from the O6-position of guanine. If inactive, it may be involved in early steps of
      colorectal tumor genesis leading to an increase of G-to-A point mutations. Epigenetic
      silencing of MGMT during colorectal tumor genesis is associated with hypermethylation of the
      CpG island in its promoter. This transcriptional gene silencing is responsible for diminished
      DNA-repair of O6-alkylguanine adducts, with the consequence of enhancing chemosensitivity to
      alkylating agents including dacarbazine and its oral prodrug temozolomide (TMZ). Previous
      phase II studies showed that TMZ induced an average objective response rate by RECIST
      criteria in 10% of heavily pre-treated patients with advanced CRC carrying MGMT promoter
      methylated tumors. Thus, MGMT methylation by methylation-specific PCR (MSP) used for patients
      screening seemed to be a necessary but not sufficient condition to identify response to TMZ.
      Digital PCR quantification of MGMT methylation refined patients' selection, with benefit
      restricted to those with highly hyper-methylated tumors. Further analysis showed that MGMT
      negative/low expression by immunohistochemistry (IHC) is found in about one third of
      MSP-methylated samples and is associated with increased response rate. However, even in
      responding mCRC patients, acquired resistance to single agent TMZ emerges rapidly and almost
      invariably within 6 months from treatment initiation.

      Immune checkpoint inhibitors have been shown to trigger durable antitumor effects in a subset
      of patients. A high number of tumor mutations (so called 'tumor mutational burden') has
      recently been found associated with increased immunogenicity (due to a high number of
      neoantigens) and improved treatment efficacy across several different solid tumors. Early
      clinical testing indicated that only 1 of 33 CRC patients had a response to anti PD-1
      treatment, in contrast to substantial fractions of patients with melanomas, renal-cell
      cancers, and lung tumors who showed benefit from PD-1 blockade. Similarly, anti CTLA-4
      treatment up today brought to unsatisfactory results in unselected mCRC patients. The
      probability of response has been ascribed to a high mutational burden (that is an elevated
      number of somatic mutations), which translates in increased number of neo-antigens. In mCRCs,
      only a small fraction of tumors (<5%) display a high mutational load and are usually
      associated with inactivation of mismatch repair genes such as MLH1, MSH2 and MSH6. Molecular
      alterations in these genes occur as an initial step in colon tumor genesis leading to the
      microsatellite instability (MSI) phenotype. Indeed, mismatch repair-deficient (dMMR)
      colorectal cancers have 10 to 100 times as many somatic mutations as mismatch
      repair-proficient colorectal cancers. Moreover, mismatch repair-deficient cancers contain
      prominent lymphocyte infiltrates, a finding consistent with an immune response. Thus,
      checkpoint inhibitors may have increased activity in dMMR/microsatellite instability-high
      (MSI-H) tumors, a hypothesis which was tested in various Phase II trials with positive
      results. On the opposite, mismatch repair proficient colorectal cancer is unresponsive to
      immune checkpoint inhibitors.

      Previous reports indicate that acquired resistance to TMZ may emerge through the induction of
      a microsatellite-instability-positive phenotype. On the other hand, TMZ by itself has been
      shown to induce an increase of mutational load in other MGMT deficient solid tumors such as
      melanoma or glioblastoma. In parallel, other studies have demonstrated that alkylating
      agents' side effects can influence the immune cell compartment by selectively depleting the
      immuno-suppressive T regulator lymphocytes (Tregs), and activating the immuno-active T
      cytotoxic lymphocytes (Tc) and natural killers (NK). The investigators recently showed that
      inactivation of MMR, driven by acquired resistance to the clinical agent temozolomide,
      increased mutational load, promoted continuous renewal of neoantigens in human colorectal
      cancers and triggered immune surveillance in mouse models.

      On all of the above grounds, the investigators hypothesize that treatment of microsatellite
      stable MGMT hypermethylated CRCs with alkylating agents could reshape the tumor genetic
      landscape by increasing the tumor mutational burden either directly (by inducing G>A
      mutations) or/and indirectly (by inactivating DNA repair genes such as MLH1, MSH2 or MSH6,
      which in turn could lead to hypermutated phenotype) therefore enhancing formation of cancer
      neoantigens and immunogenicity. TMZ treatment can also modulate the repertoire of immune
      cells (Tregs, Tc, NK) favoring T cell activation. To achieve potential sensitization to
      immunotherapy by means of TMZ-induced MSI-like status, treatment with TMZ should be active
      (i.e. inducing a SD/PR/CR).
    

Trial Arms

NameTypeDescriptionInterventions
temozolomide + nivolumab + ipilimumabExperimentalTemozolomide 150 mg/sqm daily on days 1-5 every 4 weeks, for two cycles followed by TC scan assessment: if SD/PR/CR second treatment phase with nivolumab 480 mg i.v. every 4 weeks, low-dose ipilimumab 1 mg/Kg i.v. every 8 weeks and temozolomide at the previously adopted schedule
  • Temozolomide
  • Nivolumab
  • Ipilimumab

Eligibility Criteria

        Inclusion Criteria:

          1. Have provided written informed consent prior to any study specific procedures

          2. Willing and able to comply with the protocol

          3. ≥18 years of age

          4. ECOG status 0 - 1

          5. At least 12 weeks of life expectancy at time of entry into the study

          6. Histologically confirmed metastatic or inoperable adenocarcinoma of the colon and/or
             rectum, with centrally confirmed mismatch repair proficiency (microsatellite stable
             [MSS]) by multiplex polymerase chain reaction (PCR), MGMT promoter methylation by
             methylation-specific PCR (MSP) and MGMT low expression by IHC

          7. Patients with progressive disease or that are not candidate for oxaliplatin irinotecan
             fluoropirimidin based chemotherapy and anti EGFR mAbs (in RAS/BRAF wild type tumors)
             in the metastatic setting

          8. Patients with documented disease relapsed within 6 months from the completion of
             adjuvant oxaliplatin-based chemotherapy are considered eligible

          9. Measureable, unresectable disease according to RECIST 1.1. Subjects with lesions in a
             previously irradiated field as the sole site of measurable disease will be permitted
             to enroll provided the lesion(s) have demonstrated clear progression and can be
             measured accurately.

         10. Is willing and able to provide an adequate archival tumor sample (FFPE) available for
             tissue screening for central tissue screening. If the tumour block is not available, a
             minimum of twenty 3-micron unstained sections on charged slides of tumor will be
             required.

        Exclusion Criteria:

          1. Requirement for treatment with any medicinal product that contraindicates the use of
             any of the study medications, may interfere with the planned treatment, affects
             patient compliance or puts the patient at high risk for treatment-related
             complications

          2. Inability to swallow pills

          3. Refractory nausea and vomiting, malabsorption, external biliary shunt or significant
             bowel resection that would preclude adequate absorption

          4. Inadequate haematological function indicated by all of the following:

               -  White Blood Cell (WBC) count < 2 x 109/L

               -  Absolute neutrophil count (ANC) < 1.5 x 109/L

               -  Platelet count < 100 x 109/L

               -  Haemoglobin < 9 g/dL (patients may have transfusions and/or growth factors to
                  attain adequate Hb)

          5. Inadequate liver function indicated by all of the following:

               -  Total bilirubin ≥ 1.5 x upper limit of normal (ULN)

               -  Aspartate transaminase (AST) and alanine aminotransferase (ALT) ≥ 3 x ULN (≥ 5 x
                  ULN in patients with known liver metastases)

               -  Alkaline phosphatase (ALP) ≥ 2 x ULN (≥ 5 x ULN in patients with known liver
                  metastases)

          6. Inadequate renal function indicated by all of the following:

             - Serum creatinine > 1.5 x ULN or calculated creatinine clearance < 40 ml/min

          7. INR > 1.5 and aPTT > 1.5 x ULN within 7 days prior to the start of study treatment for
             patients not receiving anti-coagulation

             a. NOTE: The use of full-dose oral or parenteral anticoagulants is permitted as long
             as the INR or aPTT is within therapeutic limits (according to the medical standard of
             the enrolling institution) and the patient has been on a stable dose of anticoagulants
             for at least two weeks prior to the start of study treatment

          8. Active infection requiring intravenous antibiotics at the start of study treatment

          9. Previous or concurrent malignancy, except for adequately treated basal or squamous
             cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate,
             cervix, or breast, or other cancer for which the patient has been disease-free for
             three years prior to study entry

         10. Evidence of any other disease, neurologic or metabolic dysfunction, physical
             examination finding or laboratory finding giving reasonable suspicion of a disease or
             condition that contraindicates the use of any of the study medications, puts the
             patient at higher risk for treatment-related complications or may affect the
             interpretation of study results

         11. Clinically significant (i.e. active) cardiovascular disease, for example
             cerebrovascular accidents ≤ 6 months prior to start of study treatment, myocardial
             infarction ≤ 6 months prior to study enrolment, unstable angina, New York Heart
             Association (NYHA) Functional Classification Grade II or greater congestive heart
             failure, or serious cardiac arrhythmia uncontrolled by medication or potentially
             interfering with protocol treatment

         12. History or evidence upon physical or neurological examination of central nervous
             system (CNS) disease (e.g. seizures) unrelated to cancer unless adequately treated
             with standard medical therapy

         13. Active brain metastases or leptomeningeal metastases. Subjects with brain metastases
             are eligible if these have been treated and there is no magnetic resonance imaging
             (MRI except where contraindicated in which CT scan is acceptable) evidence of
             progression for at least 8 weeks after treatment is complete and within 28 days prior
             to first dose of study drug administration. Cases should be discussed with the medical
             monitor. There must also be no requirement for immunosuppressive doses of systemic
             corticosteroids (>10mg/day prednisone equivalents) for at least 2 weeks prior to study
             drug administration.

         14. Surgical procedure (including open biopsy, surgical resection, wound revision, or any
             other major surgery involving entry into a body cavity) or significant traumatic
             injury within 28 days prior to start of study treatment, or anticipation of need for
             major surgical procedure during the course of the study.

         15. Treatment with any chemotherapy, curative intent radiation therapy, biologics for
             cancer, or investigational therapy within 28 days of first administration of study
             treatment (subjects with prior cytotoxic or investigational products < 4 weeks prior
             to treatment might be eligible after discussion between investigator and sponsor, if
             toxicities from the prior treatment have been resolved to Grade 1 (NCI CTCAE version
             4). Prior focal palliative radiotherapy must have been completed at least 2 weeks
             before study drug administration.

         16. All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue
             must have resolved to Grade 1 (NCI CTCAE version 4) or baseline before administration
             of study drug. Subjects with toxicities attributed to prior anti-cancer therapy which
             are not expected to resolve and result in long lasting sequelae, such as neuropathy
             after platinum based therapy, are permitted to enroll.

         17. Known hypersensitivity to any of the study medications or Known hypersensitivity or
             allergy to Chinese hamster ovary cell products or any component of the NIVO
             formulation

         18. History of severe allergic, anaphylactic, or other hypersensitivity reactions to
             chimeric or humanized antibodies or fusion proteins

         19. History of autoimmune disease including but not limited to myasthenia gravis,
             myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,
             inflammatory bowel disease, vascular thrombosis associated with antiphospholipid
             syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome,
             multiple sclerosis, vasculitis, or glomerulonephritis (see Appendix IV for a more
             comprehensive list of autoimmune diseases)

             a. Note: history of autoimmune-related hypothyroidism on a stable dose of thyroid
             replacement hormone may be eligible. Subjects with controlled type I diabetes mellitus
             on a stable insulin regimen, vitiligo or psoriasis not requiring systemic treatment
             may be eligible.

         20. Prior allogeneic bone marrow transplantation or prior solid organ transplantation

         21. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced
             pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic
             organizing pneumonia), or evidence of active pneumonitis on Screening chest CT scan

         22. Treatment with systemic immunostimulatory agents (including but not limited to
             interferons or interleukin-2) within 4 weeks or five half-lives of the drug, whichever
             is shorter, prior to start of study treatment

         23. Treatment with systemic corticosteroids (>10 mg daily prednisone equivalents) or other
             systemic immunosuppressive medications (including but not limited to prednisone,
             dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and
             anti-tumour necrosis factor [TNF] agents) within 2 weeks prior to start of study
             treatment, or requirement for systemic immunosuppressive medications during the trial.
             The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) is
             allowed.

             a. Note: Patients who have received acute, low-dose, systemic immunosuppressant
             medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled in the
             study after discussion with and approval by the Sponsor.

         24. Positive test for human immunodeficiency virus (HIV)

         25. Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg]
             test prior to randomization) or hepatitis C

               1. 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. Patients with detectable
                  HBV-DNA are not eligible.

               2. Note: Patients positive for hepatitis C virus (HCV) antibody are eligible only if
                  polymerase chain reaction testing is negative for HCV ribonucleic acid (RNA).

         26. Active tuberculosis

         27. Administration of a live, attenuated vaccine within 4 weeks prior to start of study
             treatment or anticipation that such a live attenuated vaccine will be required during
             the study

         28. Prior treatment with CD137 agonists, anti-CTLA4, anti-PD-1, or anti-PD-L1 therapeutic
             antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint
             pathways, including prior therapy with anti-tumor vaccines.

         29. Pregnancy or lactation. A serum pregnancy test is required within 7 days prior to
             start of study treatment, or within 14 days with a confirmatory urine pregnancy test
             within 7 days prior start of study treatment

         30. For women who are not post-menopausal (< 12 months of non-therapy-induced amenorrhea)
             or surgically sterile (absence of ovaries and/or uterus): refusal to use a highly
             effective contraceptive method (i.e. with a failure rate of < 1% per year such as
             sexual abstinence, hormonal implants, combined oral contraceptives, vasectomised
             partner), during the study drug administration and for at least 6 months after the
             last dose of study medication. Periodic abstinence [e.g., calendar, ovulation,
             symptothermal, postovulation methods] and withdrawal are not acceptable methods of
             contraception. A combination of male condom with cap, diaphragm or sponge with
             spermicide (double barrier methods) is not considered highly effective, birth control
             methods. Acceptable methods of contraception may include total abstinence in cases
             where the lifestyle of the patient ensures compliance. A Vasectomised partner is a
             highly effective birth control method provided that partner is the sole sexual partner
             of the trial participant and that the vasectomised partner has received medical
             assessment of the surgical success.

         31. For men: refusal to use a highly effective contraceptive method (i.e. with a failure
             rate of < 1 % per year such as vasectomy, sexual abstinence or female partner use of
             hormonal implants or combined oral contraceptives) during the study drug
             administration and for a period of at least 6 months after the last dose of study
             medication. Periodic abstinence [e.g., calendar, ovulation, symptothermal, post
             ovulation methods] and withdrawal are not acceptable methods of contraception. A
             combination of male condom with either, cap, diaphragm or sponge with spermicide
             (double barrier methods) is not considered highly effective, birth control methods.
             Acceptable methods of contraception may include total abstinence in cases where the
             lifestyle of the patient ensures compliance. A vasectomised trial participant is a
             highly effective birth control method provided that the trial participant has received
             medical assessment of the surgical success.
      
Maximum Eligible Age:99 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Evaluate the efficacy, measured as 8-month PFS rate, of the combination of temozolomide, nivolumab and ipilimumab in patients achieving disease control following 2-month lead-in treatment with single agent TMZ
Time Frame:8 months from the last patient enrolled
Safety Issue:
Description:The primary efficacy endpoint of this study is 8-month PFS rate, defined as the proportion of patients alive and progression-free at 8 months from the enrollment. Investigator-assessed PFS according to RECIST v1.1 Investigator-assessed PFS according to modified RECIST

Secondary Outcome Measures

Measure:Estimate the overall response rates (ORR) of the combination regimen of temozolomide, nivolumab and ipilimumab
Time Frame:36 months
Safety Issue:
Description:ORR measured by response rate according to RECIST 1.1 and modified RECIST criteria
Measure:Estimate duration of response (DoR) of the combination regimen of temozolomide, nivolumab and ipilimumab
Time Frame:36 months
Safety Issue:
Description:DoR assessed per RECIST 1.1 and modified RECIST
Measure:Estimate overall survival (OS) of the combination regimen of temozolomide, nivolumab and ipilimumab
Time Frame:36 months
Safety Issue:
Description:overall survival
Measure:Estimate ORR according to an Imaging Independent Central Review, using RECIST 1.1 and modified RECIST criteria
Time Frame:36 moths
Safety Issue:
Description:CD-ROM copies of the CT scans performed at baseline and during treatment until disease progression according to RECIST 1.1 and modified RECIST criteria will be collected at the Coordinating Center (S.C. Oncologia Medica 1, Fondazione IRCCS Istituto Nazionale dei Tumori) for central review
Measure:Evaluate the adverse events encountered by patients treated with the combination of temozolomide, nivolumab and ipilimumab
Time Frame:36 months
Safety Issue:
Description:Number of participants with treatment-related adverse events graded according to the NCI CTCAE v4.0
Measure:Estimate DoR of the combination regimen of temozolomide, nivolumab and ipilimumab according to an Imaging Independent Central Review
Time Frame:36 months
Safety Issue:
Description:DoR calculated after the Imaging Independent Central Review
Measure:Estimate PFS of the combination regimen of temozolomide, nivolumab and ipilimumab according to an Imaging Independent Central Review
Time Frame:36 months
Safety Issue:
Description:PFS calculated after the Imaging Independent Central Review
Measure:Assess quality of life
Time Frame:36 months
Safety Issue:
Description:QoL scale will be used to assess changes in QoL from baseline

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Trial Keywords

  • nivolumab
  • ipilimumab
  • temozolomide
  • microsatellite stable
  • MSS
  • MGMT

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