Clinical trial NCT01296113: Chemotherapy for Lung Cancer in HIV-positive Patients
Official title: Phase II Trial Evaluating the Efficacy and Safety of Carboplatin Plus Pemetrexed in Human Immunodeficiency Virus Positive (HIV+) Patients With Stage III (Not Amenable to Radiation or Inoperable) or Stage IV Nonsquamous Non Small Cell Lung Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Non-small Cell Lung Cancer
Hiv-positive
Keywords: IFCT
Lead sponsor: Intergroupe Francophone de Cancerologie Thoracique
Sponsor class: OTHER
First posted: 2011-02-15
Enrollment: 61
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a phase II, multicenter, non-randomized, open-label study evaluating the combination of pemetrexed plus carboplatin in HIV-positive patients with lung cancer.

Detailed description: The use of tritherapy in developed countries starting in 1996 led to a considerable reduction in AIDS mortality due to opportunistic infections and AIDS-defining cancers. However, increased life expectancies were accompanied by a diversification of the causes of death in HIV-infected individuals. In France between 2000 and 2005, non-AIDS-defining mortality rose from 53% to 64%: non-AIDS-defining cancers (apart from hepatocellular carcinoma) had the highest mortality rates, increasing from 11% to 17% in 2005, followed by liver disease (15% in 2005), cardiovascular disease (8% in 2005) and suicide (5%). Among all cancer-related deaths (AIDS- and non-AIDS-defining), the proportion due to non-AIDS-defining cancers (apart from hepatocellular carcinoma) increased from 38% to 50% and lung cancer (LC) accounted for 65% of deaths. Many epidemiological studies have demonstrated an elevated risk of LC in HIV-infected individuals HIV-positive subjects are younger at diagnosis of LC than the general population (45 versus 62 years). In the most recent studies, adenocarcinoma comprised 70% of cases. The prognosis of LC is worse in HIV-positive individuals. Some authors suggest that these poor outcomes may be related to interactions and additive toxicities of the cytotoxic and antiretroviral drugs. It is also likely that the disease is particularly aggressive. In the general population with a PS of 0 or 1 and under 70 years of age, bitherapy improves survival as compared to monotherapy. Survival is higher when the doublet comprises a platin. Since HIV-positive subjects with LC tend to be young, it is logical to offer them the best treatment which has demonstrated efficacy in the general population. In comparison to cisplatin, carboplatin causes less vomiting, nephrotoxicity and neurotoxicity. Survival is very slightly higher with cisplatin, but this comes at the cost of greater toxicity. Carboplatin is better tolerated in subjects with PS=2 or who are over 70 years of age

The HIV-positive population is specific in that:

* PS is more often altered but the subjects are young, which calls for a platin-based doublet.
* HAART is essential and its absorption should not be compromised by repeated vomiting which is more severe with cisplatin.
* Nephropathy occurs in 15-38% of cases; the causes are multifactorial and include the HIV virus itself and the antiretroviral drugs (Tenofovir®).
* Peripheral neuropathy is frequently related to HIV or to the antiretroviral treatments (especially didanosine or stavudine (2010 YENI report)).
* Premature ageing is seen in HIV-positive subjects; this exposes them to increased cardiovascular risk and a higher frequency of heart disease which can restrict the hyper-hydration required when using cisplatin.
* In 2010, virtually all patients are treated on an ambulatory basis whereas in the past they would have been hospitalized. Carboplatin is administered in the day hospital of all the centers, but not cisplatin.
* It is important to preserve an optimal quality of life during the first line of therapy in these patients whose life expectancy is such that very few will be eligible for a second round of therapy.

Scagliotti published a phase III trial comparing cisplatin plus pemetrexed with cisplatin plus gemcitabine in subjects \< 70 years old with advanced-stage NSCLC. Overall survival was identical in both arms but the toxicity profile was in favor of the pemetrexed arm. The combination of first-line carboplatin plus pemetrexed has been evaluated in several phase II trials, particularly in subjects with a poor PS. In contrast to the taxanes or vinorelbine, for example, pemetrexed is not metabolized by CYP450, which facilitates its use in combination with protease inhibitors and NNRTI, which respectively inhibit or induce the CYP450 system.

Ancillary study BIO-IFCT-1001 will be made. Since the samples will be small, focus will be on the biomarkers associated with multiple or specific resistance to platinum salts or to pemetrexed, particularly those more specifically found in NSCLC of nonsquamous histology. Similarly, biomarkers for which IFCT pathologists have acquired an expertise will also be favored. This expertise mainly involves, on the one hand, detecting K-Ras mutations (15-25% of ADC) and RasSF1 methylation as well as TubIII expression by immunohistochemistry (IHC) and testing for mucosecretion by PAS diastase-resistant staining, and on the other hand, evaluating ERCC1 and/or MSH2 expression and thymidylate synthase (TS) expression by IHC.

Eligibility criteria: Inclusion Criteria:

* NSCLC histologically (highly recommended) and/or cytologically confirmed, stage III (non-irradiable or inoperable) or stage IV (according to 2009 TNM classification), with other than predominantly squamous histology
* HIV seropositivity (previous or inaugural), irrespective of CD4 count or viral load
* Presence of at least one measurable lesion (RECIST v1.1)
* Subject having signed the informed consent form,
* Subject who, in the investigator's opinion, will be able to comply with the requirements and constraints of the study
* Age ≥ 18 years ≤ 75 years,
* WHO performance status: 0, 1 or 2
* Weight loss ≤ 10% of total body weight in the month before inclusion
* Estimated life expectancy ≥ 1 month,
* Covered by health insurance

Exclusion Criteria:

* Bronchial cancer already treated (other than endoscopic deobstruction)
* Cancer which is amenable to surgery or radiation (curative),
* Squamous cell lung cancer or mixed small cell and non-small cell cancer, small cell lung cancer
* Creatinine clearance (MDRD) \< 45 mL/min
* Severe hypersensitivity to any of the study products or excipients
* Severe disease or uncontrolled systemic disease (unstable or decompensated respiratory disease, cardiac, hepatic or renal disease, uncontrolled opportunistic infection)
* Significant abnormality in CBC-platelets (Hb \<9 g/dL, PNN \<1500 / mm3, platelets \< 100,000 / mm3)
* Significant abnormality in liver tests (AST, ALT \> 3x ULN, and \<5 in case of liver metastases),
* Women of childbearing age without effective contraception; pregnant or breastfeeding women
* Subject who cannot take vitamin B12, folic acid or corticosteroids
* Diffuse interstitial pneumonia
* Any geographical situation or psychological condition that precludes full understanding and compliance with the protocol

Primary outcomes:
measure: Disease-Control rate after 4 cycles
timeFrame: 3-weeks
Secondary outcomes:
Other outcomes:
Locations:
city: Aix-en-Provence
country: France
facility: Centre Hospitalier du Pays d'Aix
city: Ambilly
country: France
facility: Annemasse - CH
city: Annecy
country: France
facility: Annecy - CH
city: Avignon
country: France
facility: Avignon - CH
city: Bayonne
country: France
facility: CH de la Côte Basque
city: Besancon
country: France
facility: CHU Besancon - Pneumologie
city: Caen
country: France
facility: Caen - CHU Côte de Nacre
city: Cahors
country: France
facility: CH Cahors
city: Clermont-Ferrand
country: France
facility: CHU
city: Colmar
country: France
facility: CH
city: Compiègne
country: France
facility: CH Compiègne - Pneumologie
city: Créteil
country: France
facility: Créteil - CHI
city: Grenoble
country: France
facility: CHU Grenoble - pneumologie
city: Le Mans
country: France
facility: Le Mans - Centre Hospitalier
city: Longjumeau
country: France
facility: CH
city: Lyon
country: France
facility: Hôpital de la Croix Rousse
city: Lyon
country: France
facility: Hôpital Louis Pradel
city: Marseille
country: France
facility: APHM - Hôpital Nord
city: Montpellier
country: France
facility: Montpellier - CHRU
city: Nevers
country: France
facility: Nevers - CH
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Orléans
country: France
facility: CHR d'Orléans La Source
city: Paris
country: France
facility: APHP - Hopital Tenon - Pneumologie
city: Paris
country: France
facility: GH Paris Saint-Joseph
city: Paris
country: France
facility: Hôpital Saint Antoine
city: Paris
country: France
facility: Paris - Pitié-salpêtrière
city: Pau
country: France
facility: Pau - CH
city: Pessac
country: France
facility: Centre François Magendie - hôpital du Haut-Lévèque
city: Pierre Bénite
country: France
facility: HCL - Lyon Sud (Pneumologie)
city: Reims
country: France
facility: Reims - CHU
city: Rennes
country: France
facility: Rennes - CHU
city: Saint Brieuc
country: France
facility: Saint Brieuc - CHG
city: Strasbourg
country: France
facility: NHC - Pneumologie
city: Suresnes
country: France
facility: Suresnes - Hopital Foch
city: Thonon les bains
country: France
facility: Thonon les bains - CH
city: Toulon
country: France
facility: Toulon - CHI
city: Toulouse
country: France
facility: CHU Toulouse - Pneumologie
city: Tourcoing
country: France
facility: Tourcoing - CH
city: Tours
country: France
facility: Tours - CHU
city: Valence
country: France
facility: CH Valence
Study officials:
affiliation: AP-HP, Hôpital Tenon
name: Armelle LAVOLE, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lavole A, Chouaid C, Baudrin L, Wislez M, Raguin G, Pialoux G, Girard PM, Milleron B, Cadranel J. Effect of highly active antiretroviral therapy on survival of HIV infected patients with non-small-cell lung cancer. Lung Cancer. 2009 Sep;65(3):345-50. doi: 10.1016/j.lungcan.2008.11.018. Epub 2009 Jan 9.
citation: Lavole A, Greillier L, Mazieres J, Monnet I, Kiakouama-Maleka L, Quantin X, Spano JP, Lena H, Fraisse P, Janicot H, Audigier-Valette C, Langlais A, Morin F, Makinson A, Cadranel J; French Cooperative Thoracic Intergroup (IFCT). First-line carboplatin plus pemetrexed with pemetrexed maintenance in HIV-positive patients with advanced non-squamous non-small cell lung cancer: the phase II IFCT-1001 CHIVA trial. Eur Respir J. 2020 Aug 27;56(2):1902066. doi: 10.1183/13993003.02066-2019. Print 2020 Aug.