Patient case: 68-year-old male with colon cancer; genetic feature: MLH1 methylation suppression (microsatellite instability)

Clinical trial: International Cooperative Phase III Trial of the HIT-HGG Study Group (HIT-HGG-2013)

Summary: The HIT-HGG-2013 trial offers an innovative high-quality diagnostics and science program for children and adolescents >3 years, suffering from one of the following types of high grade gliomas:
  1. glioblastoma WHO grade IV (GBM)
  2. diffuse midlineglioma histone 3 K27M mutated WHO grade IV (DMG)
  3. anaplastic astrocytoma WHO grade III (AA)
  4. diffuse intrinsic pontine glioma (DIPG)
  5. gliomatosis cerebri (GC) For 1.-3. diagnosis has to be confirmed by neuropathological survey, for 4. and 5. diagnosis has to be confirmed by neuroradiological survey.
  In addition to standard treatment (radiotherapy and temozolomide chemotherapy) the effects of two further drugs, which have been applied to millions of children and adolescents in other indications, will be compared to each other. The aim of the trial will be to investigate whether these drugs may increase the effects of radio- and chemotherapy, resulting in a better survival of the treated patients. One of these additional drugs will be valproic acid, traditionally used for treatment of seizure disorder. The other drug will be Chloroquin, a well-established drug for Malaria treatment. Recently, scientific studies provided evidence for anti-tumoral effects of both drugs: Valproat seems to be a so-called histondeacetylase inhibitor (HDAC inhibitor), controlling important genetic processes of tumor growth. Chloroquin is an autophagy inhibitor. It prevents the shutting-down of tumor cell metabolism, a strategy to ensure survival of the whole tumor by developing a resistance against radiation and antineoplastic agents.
  Studies in cell culture, animals and first clinical trials in adults as well provided evidence for efficacy of valproic acid and chloroquine in the treatment of glioblastoma. Due to this we hope children and adolescents suffering from GBM, DMG, AA, DIPG und GC will benefit from the treatment, too. As common for clinical trials, the treatment of the patients will be settled in a randomized manner to ensure impartiality of the investigators.
  One aim of the HIT-HGG-2013 trial will be to compare the effects of Valproat and Chloroquin to each other. Additionally, the results will be compared with data of the HIT-HGG-2007 trial (children and adolescents with same diseases, only treated with simultaneous temozolomide radiochemotherapy).

Detailed description: Indication:
  First-line treatment of high grade gliomas, diffuse intrinsic pontine glioma, and gliomatosis cerebri in paediatric patients < 18 years of age.
  Background:
  Based on published results regarding the potential therapeutic benefit of adult and pediatric high grade glioma patients receiving either the histone deacetylase (HDAC) inhibitor valproic acid (VPA; Barker et al. 2013; Wolff et al. 2008, 2011; Felix et al. 2011; Su et al. 2011; Rokes et al. 2010; Masoudi et al. 2008; Guthrie et al. 2013; Weller et al. 2011) or the autophagy inhibitor chloroquine (CQ; Briceño et al. 2003, 2007; Sotelo et al. 2006) in addition to radiochemotherapy, the present trial is aimed to investigate if the addition of VPA or CQ to radiochemo- and maintenance therapy with temozolomide (Stupp et al. 2005; Cohen et al. 2011a, b) provides a survival advantage in comparison to each other and also in comparison to radiochemo- and maintenance therapy with temozolomide alone. Differences in therapeutic efficiencies between VPA and CQ will be evaluated in a randomized fashion followed by comparison with a historical patient control from the previous trial HIT-HGG-2007 with temozolomide radiochemo- and maintenance therapy alone. Besides therapeutic efficiencies as indicated by event-free survival (EFS) and overall survival (OS) treatment-related toxicities will also be analysed.
  Therapy:
  TMZ, VPA, and CQ will be studied as investigational medicinal products in the present trial.
  ▪ Trial treatment will be performed as follows: Surgery with best possible extent of tumour resection
  -  Depending on the randomisation result:
  -  Start as soon as diagnosis is confirmed with VPA 10 mg/kg/d in two daily doses as NON-RETARDED FORMULA (please use Valproat-neuraxpharm®, Valproatneuraxpharm® Lösung, Ergenyl®, Ergenyl®-Lösung or Orfiril® Saft), increase by 10 mg/kg/d once per week up until recommended target serum level of 75-100 μg/ml is reached.
  -  Start as soon as diagnosis is confirmed with CQ. Please use Resochin junior®.
  Please use the following two dosing regimes to avoid to go beyond the maximum cumulative dose of [1000 mg/kg] as recommended by the SmPC:
  1. For the whole treatment period before and after radiochemotherapy (for radiochemotherapy see dosing scheme below): 50% of the recommended maximum doses in dependence of body weight according to SmPc: 11-20 kg: ½ tablet every SECOND day (= 40.5 mg CQ phosphate/25 mg CQ every SECOND day); 21-30 kg: 1/2 tablet every day (=40.5 mg CQ phosphate/25 mg CQ every day); 31-40 kg: 1 tablet every day (= 81 mg CQ phosphate/50 mg CQ every day); 41-50 kg: 1 1/2 tablets every day (= 120.5 mg CQ phosphate/75 mg CQ every day); 51-60 kg: 2 tablets every day (= 162 mg CQ phosphate/100 mg CQ every day); 61-70 kg: 2 ½ tablets every day (= 202.5 mg CQ phosphate/125 mg CQ every day). 2. ONLY for the 6-7 weeks of radiochemotherapy: 100% of the recommended maximum doses in dependence of body weight according to SmPc: 11-20 kg: ½ tablet every day (= 40.5 mg CQ phosphate/25 mg CQ every day); 21-30 kg: 1 tablet every day (= 81 mg CQ phosphate/50 mg CQ every day); 31-40 kg: 1 1/2 tablets every day (= 120.5 mg CQ phosphate/75 mg CQ every day); 41-50 kg: 2 tablets every day (= 162 mg CQ phosphate/100 mg CQ every day); 51-60 kg: 2 ½ tablets every day (= 202.5 mg CQ phosphate/125 mg CQ every day); 61-70 kg: 3 tablets every day (= 241.5 mg CQ phosphate/150 mg CQ every day). Before and upon CQ treatment, an opthalmological examination including visus, visual fields, retinal fundus, colour vision, and cornea should at least be performed at treatment start and then every 3 months!
  -  After start of VPA or CQ induction with simultaneous radiochemotherapy
  -  Fractionated, locoregional radiotherapy, total dose 54-60 Gy
  -  Simultaneous chemotherapy with oral temozolomide, 7 days per week at 75 mg/m2/d, starting at day 1 for the entire period of radiotherapy (at maximum 49 days; oral temozolomide treatment may be started in single cases at maximum 7 days before radiotherapy if the 49 days treatment period still fully covers radiotherapy).
  -  Please, use Temodal® capsules (for oral application) and Temodal® powder (for preparation of an intravenously applicable solution).
  -  Maintenance therapy with daily VPA or CQ and
  -  four weeks after simultaneous radiochemotherapy initiation of a 5 day-course of oral temozolomide [150-200 mg/m2/d], repeated every 28 days for in total 12 courses
  -  VPA or CQ treatment is performed until day 28 of the 12. course of temozolomide.
  -  Treatment doses may vary according to available medication formulations and sizes. Thus, deviances of +/- 15% of the recommended doses may be acceptable if not stated otherwise.The starting points of treatment may also vary in single cases. Thus, deviances of +/- 7 days of the recommended time periods to start treatment may be acceptable if not stated otherwise.
  Biometry (regarding the primary objectives):
  1. Confirmatory statistical design:
  1. Difference between the treatment with additional VPA and the treatment with additional CQ with respect to EFS (two sided test). Each of those planned statistical comparisons between two groups can be considered a combination of two one-sided tests. Accordingly, a superiority of one treatment group compared to the other treatment group will be interpreted, if a significant difference will be detected.
  Adaptive design with one interim analysis planned after 87 observed events, final analysis after 173 observed events.
  2. Difference between the treatment with additional VPA and the historic sample from the HIT-HGG-2007 study with respect to EFS. Rejection of H0 will be interpreted as a significant difference between VPA treatment and the historic sample. A directional interpretation will detect either a superiority of the VPA-treatment compared to the historic sample, or a superiority of the historic sample compared to the VPA treatment sample.
  3. Difference between the treatment with additional CQ and the historic sample from the HIT-HGG-2007 study with respect to EFS. Rejection of H0 will be interpreted as a significant difference between CQ-treatment and the historic sample. A directional interpretation will detect either a superiority of the CQ-treatment compared to the historic sample, or a superiority of the historic sample compared to the CQ-treatment sample.
  Statistical tests: adaptive Log-rank test / (conventional) Log-rank test Multiple Significance level α(overall) = 5%, Power = 80%, Assumed 6 months EFS-rates = 55% vs. 70% Multiple Testing: Bonferroni-Holm adjustment will be performed.
  2. Estimated sample sizes:
  About 142 recruitments (after 87 observed events) at interim analysis, about 198 recruitments (after 173 observed events) at final analysis.
  Patient recruitment will be performed for 3.8 years. Individual follow-up (including study treatment) is required for this protocol for at least 1 year and 30 days after study entry. Long-term follow-up is strongly recommended and will be organised according to national guidelines and recommendations.
  Financial support:
  Deutsche Kinderkrebsstiftung, Bonn, Germany

Eligibility: Inclusion Criteria:
  -  Newly diagnosed, previously untreated diffuse paediatric high grade glioma with central neuropathological review including paedHGG (WHO grade IV) and anaplastic astrocytoma (WHO grade III).
  -  Newly diagnosed, previously untreated diffuse intrinsic pontine glioma with central neuroradiological review
  -  Newly diagnosed, previously untreated gliomatosis cerebri of all tumour grades with central neuroradiological review
  -  Patient ≥ 3 years and < 18 years of age at time of diagnosis
  -  Written informed consent of the patient and/or the patient's parents or legal guardian according to national laws
  Exclusion Criteria:
  -  Pre-treatment of paedHGG (WHO grade IV), anaplastic astrocytoma (WHO grade III), diffuse intrinsic pontine glioma (as confirmed by neuroradiological review), and gliomatosis cerebri (as confirmed by neuroradiological review).
  -  Known hypersensitivity or contraindication to study drugs and/or dacarbazine and/or any other 4-aminoquinoline compound (hydroxychloroquine, amodiaquine)
  -  Prior chemotherapy or radiotherapy which prevents adequate performance of radiotherapy as outlined by the present protocol. This may mainly apply to patients with secondary high grade glioma after previous malignant brain tumour, e.g. medulloblastoma, ependymoma, craniopharyngeoma. If previous treatment does not prevent the adequate performance of the outlined treatment protocol patients with secondary high grade glioma will be eligible for the present trial.
  -  Other (simultaneous) malignancies
  -  Pregnancy and / or lactation
  -  Patients who are sexually active refusing to use effective contraception (oral contraception, intrauterine devices, barrier method of contraception in conjunction with spermicidal jelly)
  -  Current or recent (within 30 days prior to start of trial treatment) treatment with another investigational drug or participation in another investigational trial. EXCEPTION: Patients may be eligible after a future amendment for a separate future targeted therapy protocol in addition to the current treatment protocol, i.e. radiotherapy and temozolomide plus VPA or CQ. These patients will then be stratified within the randomized arms of the current protocol.
  -  Clinical (e.g. a constitutional mismatch repair deficiency score ≥ 3; Wimmer et al. 2014) and/or other hints (e.g. absent intratumoral immunohistochemical expression of at least one of the MLH1, MSH2, MSH6, or PMS2 mismatch repair proteins and/or high microsatellite instability) for an underlying biallelic (constitutional) mismatch repair deficiency (bMMRD/CMMRD) or a heterozygous mismatch repair deficiency (hereditary non-polyposis colon cancer syndrome/HNPCC syndrome/Lynch syndrome): These patients and their relatives should be offered human genetic counseling and rapid genetic diagnostics to confirm or rule out these conditions. These patients might not benefit from the present study treatment but maybe from other therapeutic strategies (Bouffet et al. 2016). Since patients with clinically suspected neurofibromatosis type 1 may display similar symptoms as in CMMRD, patients with clinically suspected neurofibromatosis type
  1 should be also checked for CMMRD as suggested above.
  -  Very poor clinical condition as defined by demand of mechanical ventilation and/or demand for intravenous catecholamines and/or very severe neurological damage equivalent to a coma and/or tetraplegia with complete incapability for communication (deafness, blindness, mutism)
  -  Severe concomitant diseases (e.g. immune deficiency syndrome; known tumour predisposition syndromes which do not affect adequate performance of the trial represent no exclusion criterion a priori
  -  Known HIV positivity
  -  Severe manifest hepatic disease including hepatic porphyria as well as personal or family history of severe hepatic dysfunction, especially drug-related
  -  Severe pancreatic disease
  -  Severe hepatic disease
  -  Lethal hepatic dysfunction in a sibling during valproic acid treatment
  -  Known urea cycle defect
  -  Severe coagulation disorders (in regards to thrombopenia see prerequisite for blood cell count before starting treatment)
  -  Retinopathy and restricted visual fields (Exception: Brain tumour-related changes of visual fields)
  -  Glucose-6-phosphate dehydrogenase deficiency (favism)
  -  Myasthenia gravis
  -  Known porphyria
  -  Valproic acid as antiepileptc drug for any pre-existing epilepsy
  -  Chloroquine or hydroxycloroquine as pre-existing and ongoing medication for malaria, lupus erythematodes, or any other medical reason

Relevance to patient case: not relevant