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AzTrials

Metastatic Colorectal CancerPhase 2MAYANCT03832621

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

A Phase 2 study testing Temozolomide, Nivolumab and Ipilimumab in people with Metastatic Colorectal Cancer, run by Fondazione IRCCS Istituto Nazionale dei Tumori, Milano at 1 site in Italy.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

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. Read more about this study

Who is it for?
Ages 18 to 99 years
Conditions the study is for
Metastatic Colorectal Cancer
What is being tested?
Temozolomide, Nivolumab and Ipilimumab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
135 participants
Where
1 siteItaly
Study dates
25 Mar 2019to 30 Sep 2021
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 99 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Have provided written informed consent prior to any study specific procedures
  • Willing and able to comply with the protocol
  • ≥18 years of age
  • ECOG status 0 - 1
  • At least 12 weeks of life expectancy at time of entry into the study
  • 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
Show all 10Show fewer
  • 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
  • Patients with documented disease relapsed within 6 months from the completion of adjuvant oxaliplatin-based chemotherapy are considered eligible
  • 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.
  • 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.

Who cannot join

  • 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
  • Inability to swallow pills
  • Refractory nausea and vomiting, malabsorption, external biliary shunt or significant bowel resection that would preclude adequate absorption
  • 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
Show all 44Show fewer
  • Platelet count < 100 x 109/L
  • Haemoglobin < 9 g/dL (patients may have transfusions and/or growth factors to attain adequate Hb)
  • 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)
  • Inadequate renal function indicated by all of the following:
  • Serum creatinine > 1.5 x ULN or calculated creatinine clearance < 40 ml/min
  • 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
  • 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
  • Active infection requiring intravenous antibiotics at the start of study treatment
  • 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
  • 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
  • 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
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
  • 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)
  • 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.
  • Prior allogeneic bone marrow transplantation or prior solid organ transplantation
  • 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
  • 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
  • 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.
  • 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.
  • Positive test for human immunodeficiency virus (HIV)
  • Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test prior to randomization) 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. Patients with detectable HBV-DNA are not eligible.
  • Note: Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction testing is negative for HCV ribonucleic acid (RNA).
  • Active tuberculosis
  • 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
  • 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.
  • 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
  • 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.
  • 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.

Trial locations and contacts

1 site in 1 country.

Italy1 site

  • Fondazione IRCCS Istituto Nazionale dei Tumori

    Milan, MI, 20133

Other trials in Italy

About this study

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

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.

Read more

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.

Read the 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).

Keywords
nivolumab, ipilimumab, temozolomide, microsatellite stable, MSS, MGMT
Medical subject headings
Colorectal Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • TemozolomideDrug

    temozolomide 150 mg/sqm daily on days 1-5 every 4 weeks

  • NivolumabDrug

    nivolumab 480 mg i.v. every 4 weeks

  • IpilimumabDrug

    low-dose ipilimumab 1 mg/Kg i.v. every 8 weeks

Study groups in NCT03832621
Study groupRoleWhat they receive
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
Receives: Drug: Temozolomide; Drug: Nivolumab; Drug: Ipilimumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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

    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

    Measured: 8 months from the last patient enrolled

Secondary outcomes (8)

  1. Estimate the overall response rates (ORR) of the combination regimen of temozolomide, nivolumab and ipilimumab

    ORR measured by response rate according to RECIST 1.1 and modified RECIST criteria

    Measured: 36 months

  2. Estimate duration of response (DoR) of the combination regimen of temozolomide, nivolumab and ipilimumab

    DoR assessed per RECIST 1.1 and modified RECIST

    Measured: 36 months

  3. Estimate overall survival (OS) of the combination regimen of temozolomide, nivolumab and ipilimumab

    overall survival

    Measured: 36 months

  4. Estimate ORR according to an Imaging Independent Central Review, using RECIST 1.1 and modified RECIST criteria

    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

    Measured: 36 moths

  5. Evaluate the adverse events encountered by patients treated with the combination of temozolomide, nivolumab and ipilimumab

    Number of participants with treatment-related adverse events graded according to the NCI CTCAE v4.0

    Measured: 36 months

  6. Estimate DoR of the combination regimen of temozolomide, nivolumab and ipilimumab according to an Imaging Independent Central Review

    DoR calculated after the Imaging Independent Central Review

    Measured: 36 months

  7. Estimate PFS of the combination regimen of temozolomide, nivolumab and ipilimumab according to an Imaging Independent Central Review

    PFS calculated after the Imaging Independent Central Review

    Measured: 36 months

  8. Assess quality of life

    Quality of life will be assessed through Patient reported outcomes (PRO) instrument. PRO will be assessed by EORTC QLQ-C30 EORTC QLQ-CR29 and EuroQol EQ-5D

    Measured: 36 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted6 Feb 2019
  2. Study start25 Mar 2019
  3. Primary completion30 Sep 2021
  4. Study completion30 Sep 2021

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
135 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03832621
Sponsor's protocol ID
INT202-18
Acronym
MAYA
Status last verified
Sep 2021
First submitted
31 Jan 2019
Last updated
4 Apr 2022
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No

Publications

  • Schmoll HJ, Van Cutsem E, Stein A, Valentini V, Glimelius B, Haustermans K, Nordlinger B, van de Velde CJ, Balmana J, Regula J, Nagtegaal ID, Beets-Tan RG, Arnold D, Ciardiello F, Hoff P, Kerr D, Kohne CH, Labianca R, Price T, Scheithauer W, Sobrero A, Tabernero J, Aderka D, Barroso S, Bodoky G, Douillard JY, El Ghazaly H, Gallardo J, Garin A, Glynne-Jones R, Jordan K, Meshcheryakov A, Papamichail D, Pfeiffer P, Souglakos I, Turhal S, Cervantes A. ESMO Consensus Guidelines for management of patients with colon and rectal cancer. a personalized approach to clinical decision making. Ann Oncol. 2012 Oct;23(10):2479-2516. doi: 10.1093/annonc/mds236.

    PubMed 23012255

  • Temraz S, Mukherji D, Shamseddine A. Sequencing of treatment in metastatic colorectal cancer: where to fit the target. World J Gastroenterol. 2014 Feb 28;20(8):1993-2004. doi: 10.3748/wjg.v20.i8.1993.

    PubMed 24616571

  • Stein A, Bokemeyer C. How to select the optimal treatment for first line metastatic colorectal cancer. World J Gastroenterol. 2014 Jan 28;20(4):899-907. doi: 10.3748/wjg.v20.i4.899.

    PubMed 24574764

  • Tejpar S, Piessevaux H. Personalized medicine in metastatic colorectal cancer treated with anti-epidermal growth factor receptor agents: a future opportunity? Asia Pac J Clin Oncol. 2014 Mar;10 Suppl 1:2-10. doi: 10.1111/ajco.12176.

    PubMed 24512508

  • Bekaii-Saab T, Wu C. Seeing the forest through the trees: a systematic review of the safety and efficacy of combination chemotherapies used in the treatment of metastatic colorectal cancer. Crit Rev Oncol Hematol. 2014 Jul;91(1):9-34. doi: 10.1016/j.critrevonc.2014.01.001. Epub 2014 Jan 15.

    PubMed 24534706

  • Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouche O, Mineur L, Barone C, Adenis A, Tabernero J, Yoshino T, Lenz HJ, Goldberg RM, Sargent DJ, Cihon F, Cupit L, Wagner A, Laurent D; CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013 Jan 26;381(9863):303-12. doi: 10.1016/S0140-6736(12)61900-X. Epub 2012 Nov 22.

    PubMed 23177514

  • Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, Yamazaki K, Shimada Y, Tabernero J, Komatsu Y, Sobrero A, Boucher E, Peeters M, Tran B, Lenz HJ, Zaniboni A, Hochster H, Cleary JM, Prenen H, Benedetti F, Mizuguchi H, Makris L, Ito M, Ohtsu A; RECOURSE Study Group. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015 May 14;372(20):1909-19. doi: 10.1056/NEJMoa1414325.

    PubMed 25970050

  • Oberg A, Samii S, Stenling R, Lindmark G. Different occurrence of CD8+, CD45R0+, and CD68+ immune cells in regional lymph node metastases from colorectal cancer as potential prognostic predictors. Int J Colorectal Dis. 2002 Jan;17(1):25-9. doi: 10.1007/s003840100337.

    PubMed 12018450

  • Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoue F, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Pages F. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006 Sep 29;313(5795):1960-4. doi: 10.1126/science.1129139.

    PubMed 17008531

  • Pages F, Kirilovsky A, Mlecnik B, Asslaber M, Tosolini M, Bindea G, Lagorce C, Wind P, Marliot F, Bruneval P, Zatloukal K, Trajanoski Z, Berger A, Fridman WH, Galon J. In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J Clin Oncol. 2009 Dec 10;27(35):5944-51. doi: 10.1200/JCO.2008.19.6147. Epub 2009 Oct 26.

    PubMed 19858404

  • Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010 Aug 19;363(8):711-23. doi: 10.1056/NEJMoa1003466. Epub 2010 Jun 5.

    PubMed 20525992

  • Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):908-18. doi: 10.1016/S1470-2045(15)00083-2. Epub 2015 Jun 23.

    PubMed 26115796

  • Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Aren Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015 Jul 9;373(2):123-35. doi: 10.1056/NEJMoa1504627. Epub 2015 May 31.

    PubMed 26028407

  • Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012 Jun 28;366(26):2443-54. doi: 10.1056/NEJMoa1200690. Epub 2012 Jun 2.

    PubMed 22658127

  • Lipson EJ, Sharfman WH, Drake CG, Wollner I, Taube JM, Anders RA, Xu H, Yao S, Pons A, Chen L, Pardoll DM, Brahmer JR, Topalian SL. Durable cancer regression off-treatment and effective reinduction therapy with an anti-PD-1 antibody. Clin Cancer Res. 2013 Jan 15;19(2):462-8. doi: 10.1158/1078-0432.CCR-12-2625. Epub 2012 Nov 20.

    PubMed 23169436

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Temozolomide, Nivolumab and Ipilimumab in people with Metastatic Colorectal Cancer, run by Fondazione IRCCS Istituto Nazionale dei Tumori, Milano at 1 site in Italy.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 10 inclusion and 44 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 4 Apr 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome 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). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03832621, which also lists 57 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Apr 2022.

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