Neoplasms

Symptoms and General Pathology

All Conditions

Digestive System Diseases

Neoplasm, Residual

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Antineoplastic Agents

All Drugs and Chemicals

Irinotecan

Temozolomide

Topoisomerase I Inhibitors

Enzyme Inhibitors

Antineoplastic Agents, Alkylating

Alkylating Agents

Irinotecan intravenous infusion (IV) given every 14 days in combination with oral (PO) temozolomide over days 1-5 every 28 days.

The treatment will consist of six 28-days cycles of TEMIRI.

Irinotecan 100 mg/smq intravenous infusion every 14 days

Oral temozolomide 150 mg/sqm over days 1-5 every 28 days.

Filippo Pietrantonio, MD

Federica Morano, MD

Surgical resection is curative for 75% of stage II and 50% of stage III colon cancer patients. The magnitude of benefit of adjuvant chemotherapy in terms of disease-free (DFS) and overall survival (OS) varies according to TNM stage and microsatellite status. Standard adjuvant chemotherapy includes fluoropyrimidine and oxaliplatin regimens for up to six months.

Circulating tumor DNA (ctDNA) detected after surgical resection reflects the presence of micrometastatic disease and pivotal observational studies addressed the prognostic value of ctDNA in the post-surgical setting. Adjuvant chemotherapy can promote the clearance of ctDNA, and ctDNA clearance after adjuvant chemotherapy is prognostic for better DFS in patients with stage III resected cancers and post-operative positive ctDNA.

ctDNA may be investigated as a potential real-time surrogate biomarker of the efficacy of adjuvant therapy, but suggest that patients with ctDNA persistence after standard chemotherapy might be "molecularly metastatic" and may benefit from additional "consolidation" non-cross resistant strategies aimed at clearing micrometastatic disease.

Temozolomide has modest but non-negligible activity (about 10%) in chemo-refractory patients with MGMT methylated mCRC. The response rate to temozolomide-based therapy in pretreated patients is increased to up to 20% when restricting the focus on those with MGMT IHC-negative/MGMT methylated and MSS cancers Significant activity (ORR 26%) and favorable safety profile were reported by the combination of temozolomide and irinotecan (TEMIRI regimen) in patients with pretreated MGMT methylated/MSS mCRC, thus suggesting that the two agents may have synergist activity in line with preclinical data.

Based on all these considerations, there is a strong rationale for investigating TEMIRI regimen as consolidation non-cross resistant therapy in a liquid-biopsy driven interventional trial.

Eligible patients with MGMT-silenced, MSS, radically resected CRC and detectable ctDNA after standard chemotherapy will be enrolled and will receive 6-month post-adjuvant/consolidation TEMIRI (given for up to 6 monthly cycles).

Surgical resection is curative for 75% of stage II and 50% of stage III colon cancer patients. The magnitude of benefit of adjuvant chemotherapy in terms of disease-free (DFS) and overall survival (OS) varies according to TNM stage and microsatellite status. Specifically, in patients with stage II microsatellite stable (MSS) tumors and high risk clinical features (i.e. pT4, lymphovascular invasion, perineural invasion, bowel obstruction, positive surgical margins and inadequately sampled lymph nodes) adjuvant therapy with fluoropyrimidines conditioned a modest but significant DFS benefit, while oxaliplatin-based therapy may be offered to patients with poor prognosis such as those with pT4 disease. In patients with stage III disease adjuvant therapy with oxaliplatin and fluoropyrimidine combinations significantly improved DFS and OS in phase 3 randomized trials. However, oxaliplatin is burdened by dose-cumulative and potentially long-lasting neurotoxicity. Therefore, three-month duration of oxaliplatin-based chemotherapy was compared to six-month in six randomized trials including patients with resected stage (II)/III colon cancer. In the pooled analysis of such trials (IDEA Collaboration), the non-inferiority for DFS of three months adjuvant oxaliplatin-based chemotherapy was not formally demonstrated. However, absolute DFS loss with 3- month therapy was clearly unsignificant from a clinical point-of-view and 3-month duration of oxaliplatin-based adjuvant chemotherapy is now recommended in patients with low risk disease (pT3N1) and particularly when adopting a capecitabine-based regimen (CAPOX).

Circulating tumor DNA (ctDNA) detected after surgical resection reflects the presence of micrometastatic disease and pivotal observational studies addressed the prognostic value of ctDNA in the post-surgical setting. Detectable ctDNA after surgery is prognostic for DFS in patients with resected colon cancer with high specificity in predicting recurrence (-100%), reinforcing its promising role for guiding trials on post-surgical intensification strategies, but ctDNA is also endowed with suboptimal sensitivity (70%), thus limiting its potential usefulness to guide the complete omission of adjuvant chemotherapy. Regarding the impact of adjuvant chemotherapy on micrometastatic disease, adjuvant chemotherapy was able to clear ctDNA in individual patients with resected stage II tumors. Moreover, ctDNA clearance after adjuvant chemotherapy was prognostic for better DFS in patients with stage III resected cancers and post-operative positive ctDNA. Collectively, these data highlight that ctDNA may be investigated as a potential real-time surrogate biomarker of the efficacy of adjuvant therapy, but suggest that patients with ctDNA persistence after standard chemotherapy might be "molecularly metastatic" and may benefit from additional "consolidation" non-cross resistant strategies aimed at clearing micrometastatic disease.

Temozolomide displayed limited activity (overall response rate \[ORR\] 9%) in patients with heavily pretreated metastatic colorectal cancer (mCRC) with MGMT promoter methylation assessed by means of a qualitative assay - methylation-specific PCR. However, even if MGMT promoter methylation is found in up to 40% of patients with colorectal cancer, in-silico analyses and translational analyses showed that only a subset of these tumors (- 10% of all comers) display lack of MGMT expression and negative MGMT IHC staining. In keeping with findings, correlative studies of phase 2 trials showed that MGMT immunohistochemical negativity and higher MGMT methylation % by quantitative assays are associated with temozolomide activity. Finally, proficiency of the mismatch repair is needed for alkylators activity. Therefore, temozolomide might be considered a tailored chemotherapy in patients with MGMT silenced tumors (i.e. those with MGMT negative expression and MGMT promoter methylation) and microsatellite stable (MSS) tumors. Significant activity (ORR 26%) and favorable safety profile were reported by the combination of temozolomide and irinotecan (TEMIRI regimen) in patients with pretreated MGMT methylated/MSS mCRC, thus suggesting that the two agents may have synergist activity in line with preclinical data.

Moving from this rationale we designed a phase 2 proof-of-concept trial aimed at evaluating the activity in terms of ctDNA clearance or "seroreversion" after TEMIRI regimen as a post-adjuvant strategy in patients with MGMT silenced, MSS colorectal cancer (CRC) with positive ctDNA after oxaliplatin-based adjuvant standard chemotherapy.

Eligible patients with MGMT-silenced, MSS, radically resected CRC and detectable ctDNA after standard chemotherapy will be enrolled and will receive 6-month post-adjuvant/consolidation TEMIRI (given for up to 6 monthly cycles).

Temozolomide and Irinotecan in Patients With MGMT Silenced Colorectal Cancer After Adjuvant Chemotherapy

Temozolomide and Irinotecan Consolidation in Patients With MGMT Silenced, Microsatellite Stable Colorectal Cancer With Persistence of Minimal Residual Disease in Liquid Biopsy After Standard Adjuvant Chemotherapy: the ERASE-TMZ Study

To develop a gene expression signature (a single or combined group of genes) associated with temozolomide resistance/sensitivity by profiling tumor tissue blocks obtained prior to any treatment

To longitudinally monitor the disease recurrence thanks to serial liquid biopsies obtained during the follow-up phase. The outcome will be measured as the percentage of ctDNA negative patients with recurrence disease

The activity of TEMIRI will be measured as the rate of patients with post-treatment seroreversion and disease-free at 2 years

DFS is defined as the time from randomization to recurrence of tumor or death due to any cause, whichever occurs first. DFS will be censored on the date of the last evaluable on study tumour assessment documenting absence of disease relapse for patients who are alive and disease-free at the time of the analysis. Alive patients having no tumour assessments after baseline will have time to event censored on the data of enrolment

OS is defined as the time from enrolment to the date of death due to any cause. For patients still alive at the time of analysis, the OS time will be censored on the last date the patients were known to be alive.

Safety will be assessed by monitoring the frequency of adverse events

EORTC QLQ-C30 administered every 12 weeks during treatment and at the date of first documented progression, assessed up to 24 months from enrollment

EORTC QLQ-CR29 administered every 12 weeks during treatment and at the date of first documented progression, assessed up to 24 months from enrollment

EQ-5D-5L administered every 12 weeks during treatment and at the date of first documented progression, assessed up to 24 months from enrollment

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Skin and Connective Tissue Diseases

Rare Diseases

Sarcoma

Sarcoma, Ewing

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Osteosarcoma

Neoplasms, Bone Tissue

Neoplasms, Connective Tissue

Soft Tissue Sarcoma

Ewing Sarcoma

Antirheumatic Agents

Etoposide

Cyclophosphamide

Doxorubicin

Liposomal doxorubicin

Vincristine

Melphalan

Ifosfamide

Etoposide phosphate

Busulfan

Vinblastine

Isophosphamide mustard

Patients in Arm A receive

* VDC-IE x2: Intensified induction phase:

  * 4 cycles of VDC (Vincristine Doxorubicine Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association if "good response" after the 4th treatment, followed by:
  * 4 cycles of VDC (Vincristine-Doxorubicine-Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association
* Consolidation BuMel High dose chemotherapy (Busulfan Melphalan) followed by Peripheral Blood Stem Cell Infusion
* Local treatment by surgery of primary tumour/metastatic sites (outside pulmonary sites): indicated before of after consolidation phase (BuMel) among multidisciplinary decision. Radiotherapy can be added
* Maintenance phase

  * 1st year : VC (Vincristine Cyclophosphamide) association
  * 2nd year : Cyclophosphamide po 25 mg/m²

Patients in Arm B receive

* VDC-IE \& TEMIRI: Intensified induction phase:

  * 4 cycles of VDC (Vincristine-Doxorubicine-Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association if "poor response" after the 4th treatment, followed by:
  * 4 cycles of TEMIRI (Temozolomide-Irinotecan) association
* Local treatment by surgery of primary tumour/metastatic sites (outside pulmonary sites): indicated before of after consolidation phase (BuMel) among multidisciplinary decision. Radiotherapy can be added
* Consolidation BuMel High dose chemotherapy (Busulfan-Melphalan) followed by Peripheral Blood Stem Cell Infusion
* Maintenance phase

  * 1st year : VC (Vincristine Cyclophosphamide) association
  * 2nd year : Cyclophosphamide po 25 mg/m²

Patients in Arm C receive

* VDC-IE x2: Intensified induction phase:

  * 4 cycles of VDC (Vincristine-Doxorubicine-Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association if "good response" after the 4th treatment, followed by:
  * 4 cycles of VDC (Vincristine-Doxorubicine-Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association
* Consolidation BuMel High dose chemotherapy (Busulfan-Melphalan) followed by Peripheral Blood Stem Cell Infusion
* Local treatment by radiotherapy of primary tumour/metastatic sites (outside pulmonary sites): indicated before of after consolidation phase (BuMel) among multidisciplinary decision.
* Consolidation BuMel High dose chemotherapy (Busulfan-Melphalan) followed by Peripheral Blood Stem Cell Infusion
* Maintenance phase

  * 1st year : VC (Vincristine Cyclophosphamide) association
  * 2nd year : Cyclophosphamide po 25 mg/m²

Patients in Arm D receive

* VDC-IE \& TEMIRI: Intensified induction phase:

  * 4 cycles of VDC (Vincristine-Doxorubicine-Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association if "poor response" after the 4th treatment, followed by:
  * 4 cycles of TEMIRI (Temozolomide-Irinotecan) association
* Local treatment by radiotherapy of primary tumour/metastatic sites (outside pulmonary sites): indicated before of after consolidation phase (BuMel) among multidisciplinary decision.
* Consolidation BuMel High dose chemotherapy (Busulfan-Melphalan) followed by Peripheral Blood Stem Cell Infusion
* Maintenance phase

  * 1st year : VC (Vincristine Cyclophosphamide) association
  * 2nd year : Cyclophosphamide po 25 mg/m²

Week 1, 5, 9 and week 13:

* Vincristine, IV, D1, 1.5mg/m²
* Doxorubicine, IV, D1-D2, 37.5mg/m²
* Cyclophosphamide, IV, D1, 1.2g/m²

Week 3, 7, 11 and week 15:

* Ifosfamide, IV, D15 to D19, 1.8g/m²/d
* Etoposide, IV, D15 to D19, 100mg/m²/d

VDC-IE x2

Week 1 and week 5:

* Vincristine, IV, D1, 1.5mg/m²
* Doxorubicine, IV, D1-D2, 37.5mg/m²
* Cyclophosphamide, IV, D1, 1.2g/m²

Week 3, and week 7:

* Ifosfamide, IV, D15 to D19, 1.8g/m²/d
* Etoposide, IV, D15 to D19, 100mg/m²/d

VDC-IE

Week 9, 12, 15 and week 18:

* Temozolomide, PO, D1 to D5, 150mg/m²/d
* Irinotecan, IV, D1 to D5, 50mg/m²/d

TEMIRI

After induction phase and local treatment (surgery and/or radiotherapy) and before PBSC:

* Busulfan, IV, D-5 to D-2, dosa according to the weight
* Melphalan, IV, D-1, 140 mg/m²

Peripheral Blood Stem Cell infusion:

- PBSC infusion, D0, at least 3.10\^6 CD34/kg

Consolidation BuMel

\* 1st year : VC

* Vinblastine, IV, 3mg/m², once a week (except during radiotherapy: 1mg/m², 3 times a week)
* Cyclophosphamide, PO, 25mg/m² continuously

Maintenance

Surgical excision of whole site of the primary tumour and metastatic sites (outside pulmonary sites) can take place before or after the high dose consolidation chemotherapy. Radiotherapy can be added

Local treatment by surgery

Radiotherapy of whole site of the primary tumour and metastatic sites (outside pulmonary sites) can take place before or after the high dose consolidation chemotherapy

Local treatment by radiotherapy

Valérie LAURENCE, MD

Nadège CORRADINI, MD

Ewing's sarcoma and related tumours (ESFT) are rare tumours, with a peak incidence in the second decade of life. They start most often from bone, and are characterized by a specific translocation involving the so-called EWS gene. In one patient out of three, the staging procedures detect metastatic tumours at the diagnosis, most commonly in lungs, bones, and bone marrow.

ESFT treatment strategy is multidisciplinary, combining primary chemotherapy, a local treatment, and consolidation chemotherapy.

The primary metastatic dissemination is the most important prognostic factor, as the survival rate is around 70-75% for localized tumours, in contrast with less than 50% for patients with primary metastatic disease.

Among primary metastatic patients, bone involvement and / or bone marrow strike markedly the prognosis of these patients. While the long-term survival of patients with isolated pleural pulmonary metastases is approximately 50%, whereas it is only from 0 to 25% in patients with bone marrow involvement.

In 1999, the Intergroup EURO EWING built a new study protocol for patients with Ewing tumours. For the patients with primary extrapulmonary metastatic Ewing tumours (R3 patients), the protocol proposed a heavy induction chemotherapy, in order to propose a consolidation with high dose chemotherapy to a higher rate of patients. The high-dose Busulfan Melphalan chemotherapy (BuMel) was based on Busulfan (600 mg/m²) and Melphalan (140 mg/m²), with autologous peripheral blood stem cell (PBSC) support.

Of note, for the full population of patients with metastatic disease, the 3-year EFS rate was 27% (SD 3%), and the OS rate was 34% (SD 4%), with a median follow-up of 3.9 years after diagnosis, and a median survival time of 1.6 years.

Ewing's sarcoma and related tumours (ESFT) are rare tumours, with a peak incidence in the second decade of life. They start most often from bone, and are characterized by a specific translocation involving the so-called EWS gene. The gene rearrangement results in the production of a transcription factor, in the majority EWS-FLI1 transcription.

In one patient out of three, the staging procedures detect metastatic tumours at the diagnosis; metastases involve most commonly lungs, bones, and bone marrow.

Therefore, in addition to local imaging, the initial extension assessment of any Ewing tumour includes at least a chest CT scan, and a bone marrow extensive evaluation, comprising bone marrow punctures into several different sectors, bone marrow biopsies, and a bone imaging evaluation. The FDG-PET scan is more sensible than bone scan and conventional imaging as MRI in detection of bone metastases. It is more and more widely used in the bone metastasis search in Ewing tumours and seems useful to complement the search of extra-osseous metastases (outside the lungs), including that of bone marrow metastases. The full-body MRI is still under evaluation for the disease extension evaluation.

ESFT treatment strategy is multidisciplinary, combining primary chemotherapy, a local treatment, and consolidation chemotherapy. The local treatment may combine surgery and / or radiotherapy, according to the tumour site and size, and to the tumour response. ESFT chemotherapy is based on alkylating agents (ifosfamide and / or cyclophosphamide), etoposide, anthracyclines, vincristine, and actinomycin.

The primary metastatic dissemination is the most important prognostic factor, as the survival rate is around 70-75% for localized tumours, in contrast with less than 50% for patients with primary metastatic disease. Among primary metastatic patients, bone involvement and / or bone marrow strike markedly the prognosis of these patients. While the long-term survival of patients with isolated pleural pulmonary metastases is approximately 50%, whereas it is only from 0 to 25% in patients with bone marrow involvement.

In 1999, the Intergroup EURO EWING built a new study protocol for patients with Ewing tumours, localized or metastatic and below 50 years of age. For the patients with primary extrapulmonary metastatic Ewing tumours (R3 patients), the protocol proposed a heavy induction chemotherapy, in order to propose a consolidation with high dose chemotherapy to a higher rate of patients. The high-dose BuMel chemotherapy was based on Busulfan (600 mg/m²) and Melphalan (140 mg/m²), with autologous peripheral blood stem cell (PBSC) support.

The study enrolled 281 patients with primary dissemination and skeletal metastases, with or without bone marrow involvement and with or without additional pulmonary metastases or metastases to other sites. In contrast to the distribution in the entire group of patients with Ewing tumours, the primary site in this subgroup was extremity in only 31% patients, pelvis/abdomen in 45%, and axial/other in 24% patients. The overall survival at 3 years was 28% (SD 4%) in the group with primary tumour in the abdomen or pelvis, versus 39% (SD 6%) for each of the two other groups. Of note, for the full population of patients with metastatic disease, the 3-year EFS rate was 27% (SD 3%), and the OS rate was 34% (SD 4%), with a median follow-up of 3.9 years after diagnosis, and a median survival time of 1.6 years.

First-line Treatment of Ewing Tumours With Primary Extrapulmonary Dissemination in Patients From 2 to 50 Years

CombinaiR3 - First-line Treatment of Ewing Tumours With Primary Extrapulmonary Dissemination in Patients From 2 to 50 Years

Sponsor will share de-identified data sets. Documents generated under the project will be disseminated in accordance with Institut Curie policies.

EFS is defined as the time from inclusion date to the first documentation of progression, distant disease, second cancer or death (or last news for patients free of event). The event free survival is estimated by Kaplan-Meier method.

Number of patients with complete response (CR) / partial response (PR) eligible for consolidation phase

Number of patients eligible for consolidation phase have good response after induction phase :

* complete remission on primary tumour and on metastatic sites or
* very good disease response defined by:

  * complete or partial response according to RECIST 1.1 criteria on primary lesion
  * complete or very good partial response (\> 90 %) in case of RECIST 1.1 criteria on metastatic sites AND
  * complete metabolic response in case of metastatic visceral and/or bone/bone marrow lesions, or very good partial response according to investigator's judgment AND
  * in case of bone marrow involvement, bone marrow free of disease on at least one biopsy and two punctures at different sites at RE1 (evaluation after 4 cycles VDC-IE), RE2 (evaluation after 2x4 cycles VDC-IE or 4 cycles VDC-IE+4 cycles TEMIRI), or at the latest RE3 evaluation (evaluation after local treatment).

The overall survival (OS) is estimated by Kaplan-Meier method.

Number of patients with treatment-related adverse events using the NCI CTCAE version 4.03 to graduate the severity of adverse events

Number of patients with treatment-related toxicities on laboratory data using the NCI CTCAE version 4.03 to graduate the severity of toxicities

Efficacy assessed by primary tumour uptake (Standardized Uptake Value max at 18F-FDG PET)

Efficacy assessed by metabolic tumour volume (MTV at 18F-FDG PET)

sample collected : primary tumour and metastatic site (if possible)

Investigation whether the cells from metastatic material harbour a unique transcriptomic signature compared to primary tumour cells : quantification of EWS-ETS transcript and EWS-ETS gene using Polymerase Chain Reaction (PCR) methods to determine the genomic EWS-ETS translocation loci

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Temozolomide and Irinotecan in Patients With MGMT Silenced Colorectal Cancer After Adjuvant Chemotherapy	NCT05031975	Colorectal Canc...	Irinotecan Temozolomide	18 Years -	Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
First-line Treatment of Ewing Tumours With Primary Extrapulmonary Dissemination in Patients From 2 to 50 Years	NCT03011528	Ewing Sarcoma F...	VDC-IE x2 VDC-IE TEMIRI Consolidation B... Maintenance Local treatment... Local treatment...	2 Years - 50 Years	Institut Curie
Temozolomide and Irinotecan in Patients With MGMT Silenced Colorectal Cancer After Adjuvant Chemotherapy	NCT05031975	Colorectal Canc...	Irinotecan Temozolomide	18 Years -	Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Spots Global Cancer Trial Database for temiri

Every month we try and update this database with for temiri cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for temiri

Every month we try and update this database with for temiri cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for temiri cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.