BrEPEM-LH-22017 for Older Patients With Untreated Hodgkin Lymphoma (HL)

The purpose of the phase Ib of the study is to identify the maximum tolerated dose (MTD) of Brentuximab Vedotin (BV) in combination with EPEM and to assess the toxicity of the combination of BV with EPEM. In the phase II efficacy will be evaluated.Besides, progression-free survival (PFS), event-free survival (EFS), overall survival (OS), the duration of response, the overall response rate (ORR) based on best response will be evaluated

Hodgkin lymphoma (HL) is a lymphoid neoplasm characterized by the presence of CD30-positive Hodgkin Reed-Sternberg cells in a background of inflammatory cells. The majority of patients with HL have a good outcome with first-line chemotherapy such as ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine,procarbazine and prednisone) sometimes combined with radiation therapy. However, the same lymphoma has different results in the older than 60 years-old patients. This population of 60 years of age or older accounts for 20% of all HL cases. Age at diagnosis is an independent adverse prognostic factor for HL. The poor outcome in this group is due to both toxicity of chemo and radiotherapy resulting in higher treatment-related mortality and insufficient dosing of the applied treatment.

Most clinical trials exclude older patients with HL because older patients have more unfavorable risk profiles and the approaches to treat older patients with HL with intensive regimens resulted in treatment associated mortality of up to 21%. More effective treatments to get better results in this patient population are required.

In 2001 the problem about the need for effective treatments with acceptable toxicity for the older patients with HL was discussed. After that different international groups accepted the challenge of trial organization for older patients with HL.

Two phase 2 studies were developed with modified chemotherapy regimens. The first, BACOPP (Bleomycin, doxorubicin, Cyclophosphamide, vincristine, prednisolone and procarbazine), was a BEACOPP regimen modified, used in younger patients. In this study, 65 patients with early unfavorable or advanced stage HL aged between 60 and 75 years were included.

Eighty-five percent of patients achieved complete remission, 3% achieved partial remission, and 7% developed progressive disease. Eighteen patients died (30%), including 7 treatment-associated deaths. This chemotherapy regimen although was effective, had an important toxicity in this older HL patient population. The second trial was PVAG (regimen composed of gemcitabine, prednisone, vincristine and adriamycin). The treatment was used in elderly HL patients in early unfavorable and advanced stages. Fifty-nine patients were enrolled in this study; 78% of patients achieved complete remission (CR) o CR uncertain; 3,4% responded with partial response; 25% didn't achieve a response or relapsed. Seventeen deaths were observed, but only 1 of them was secondary to treatment-related toxicity.

The VEPEMB phase II study (vinblastine, cyclophosphamide, prednisolone, procarbazine, etoposide, mitoxantrone and bleomycin) was also developed. For VEPEMB study, 105 HL patients over 65 years of age were treated, of which 48 were early stage (IA-IIA) HL patients and 57 were advanced stage (IIB-IV) HL patients. CR was achieved in 98% of early stage and 58% of advanced stage HL patients. Five-year actuarial OS rate was 94% in early stage and 32% in advanced stage HL patients. Two patients died during the treatment induction, but not related to treatment toxicity In the United Kingdom, the VEPEMB treatment was adopted in the new SHIELD (Study of Hodgkin in the Elderly Database) program, that was a prospective study made up of two components: I.) a phase II trial with VEPEMB treatment and II.) a prospective registration study of patients no treated as part of the VEPEMB study. One hundred and seventy-five patients were enrolled in this program, 103 patients received VEPEMB treatment and 72 patients received other therapies (ABVD regimen, CHOP, CLVPP regimen, etc). In this study, 74% of CR in early stage and 61% of CR in advanced stage in older HL patients were observed with the VEPEMB treatment. Three-year overall survival (OS) and progression-free survival (PFS) were 81% and 74% respectively. Of patients achieving CR, 13% with early-stage and 5% with advanced-stage disease progressed. The overall treatment-related mortality was 7%. VEPEMB has demonstrated minimal pulmonary toxicity in this study, (only 1 patient). This therapeutic regimen provides adequate disease control in elderly patients with HL, with acceptable toxicity and sustained remission in those who have a complete response.

Brentuximab vedotin (BV) is an antibody-drug conjugate (ADC) consisting of three components: a) the chimeric anti-CD30 antibody cAC10, b) Monomethylauristatin E (MMAE) and c) a protease-cleavable linker that attaches MMAE to cAC10. Binding of BV to cells is followed by internalization of the ADC and cleavage of the peptide linker by lysosomal enzymes, and subsequent release of MMAE, an antimitotic agent, blocks the polymerization of tubulin, resulting in G2/M phase growth arrest and apoptotic death in a way similar to taxanes.

Moreover, due to membrane permeability of MMAE, a possible cytotoxic effect on bystander malignant cells and surrounding stroma may occur. In vivo, BV inhibits proliferation, induces apoptosis and complete tumor regression in mouse xenograft models of both HL and anaplastic large cell lymphoma (ALCL) with improved efficacy relative to the unconjugated antibody.

First Phase I trial was made in patients with relapsed/refractory CD30 positive lymphomas. Brentuximab vedotin was administered every 3 weeks at doses escalating from 0,1 to 3,6 mg/kg. Forty-five patients were treated in this study. Ninety-three percent of the patients had classical Hodgkin lymphoma.

The maximum tolerated dose (MTD) for doses every 3 weeks was defined as 1,8mg/kg and the dose-limiting toxicities were febrile neutropenia, prostatitis. Objective responses were observed in 17 patients including 11 CR.

A pivotal open-label, single arm Phase II trial studied the efficacy and safety of BV in patients with relapse or refractory HL after autologous stem-cell transplantation (ASCT). The used dose was 1,8mg/kg intravenously every 3 weeks for a maximum of 16 infusions. One hundred two patients were enrolled with a median age of 31 years. The ORR was 75% and 34% of patients achieved a CR. The median duration of response was 6.7months and it increased up 20.5 months for patients who achieved a CR.

The most common treatment-related adverse events (AEs) occurring in \>10% of all patients were peripheral neuropathy (PN) (42%), nausea (35%), fatigue (34%), neutropenia (19%), diarrhea (18%), pyrexia (14%), vomiting (13%), arthralgia (12%), pruritus (12%), myalgia (11%), peripheral motor neuropathy (11%) and alopecia (10%).

The combination of BV with ABVD and AVD chemotherapeutic regimens was investigated in a phase I study in 51 untreated patients with HL. The maximum tolerated dose of BV combined with ABVD or AVD was not reached and no DLT was observed up to 1.2 mg/kg every 2 weeks.

However, an increased incidence of pulmonary toxicity was observed with the association with bleomycin. Ninety-two percent of patients achieved CR which compares favorably with historical controls. A phase 3 study comparing BV combined with AVD versus ABVD alone is ongoing.

Based on the previous phase I study of Younes of the combination of BV with ABVD or AVD therapy, no dose-limiting toxicity were observed with 1.2 mg/Kg of BV, and the maximum tolerated dose was not exceeded at 1.2 mg/Kg of BV combined with ABVD or AVD. Since the combination of BV and EPEM has not been tested before a safety run in stage phase is added to the protocol.

Eligibility Criteria:
Inclusion Criteria:

1. Males or females of 60 years of age or older.
2. Previously untreated classical Hodgkin lymphoma (i.e., nodular sclerosis, mixed cellularity, lymphocyte depleted, lymphocyte-rich, and not otherwise specified \[NOS\]).
3. Stage IIB, III, and IV disease by Ann Arbor classification.
4. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2.
5. Patients must have bi-dimensional measurable disease documented in the lymphoma baseline tumor assessment form (PET-CT report) within 30 days prior to Screening (at least 1.5 cm)
6. Patients must have a bone marrow biopsy within 60 days prior to screening.
7. Patients must have a multi gated acquisition scan (MUGA) or echocardiogram within 60 days prior to study screening and the ejection fraction must be \>= 50%.
8. Adequate hematologic function, defined as Absolute neutrophil count (ANC) ≥ 1,500/mm3 / 1x109/L and Platelet count ≥75,000/mm3 / 75x109/L unless there is known marrow involvement of the disease
9. Serum Creatinine \< 2.0 mg/dl and/or creatinine clearance or calculated creatinine clearance \> 40 mL/minute.
10. Total Bilirubin \< 1.5 x the upper limit of normal (ULN) unless elevation is known to be due to Gilbert syndrome.
11. ALT or AST must be \< 3 x the upper limit of the normal range. AST and ALT may be elevated up to 5 times the ULN if their elevation can be reasonably ascribed to the presence of hematologic/solid tumour in liver.
12. Hemoglobin must be ≥ 8g/dL
13. Patients must not have received prior chemotherapy or radiation therapy for the treatment of Hodgkin lymphoma.
14. Female patient is either post-menopausal for at least 2 years before the screening visit or surgically sterile or if of childbearing potential must agree to use two effective contraceptive methods, at the same time, from the time of signing the informed consent and for 6 months following the last dose of study drug, or agree to completely abstain from heterosexual intercourse.
15. Male patients, even if surgically sterilized, (i.e., status post vasectomy) must agree to practice effective barrier contraception during the entire study period and through 6 months after the last dose of study drug, or agree to completely abstain from heterosexual intercourse.
16. Patients must sign the informed consent form before screening. Voluntary written informed consent must be signed before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.

Exclusion Criteria:

1. Nodular lymphocyte predominant Hodgkin lymphoma
2. Previous treatment with BV or any other prior anti-CD30-based antibody therapy
3. Female patient who is both lactating and breast-feeding or has a positive pregnancy test during the screening period or a positive pregnancy test on Day 1 before the first dose of study drug
4. History of another primary malignancy that has not been in remission for at least 3 years; (the following are exempt from the 3-year limit: early stage \[stage I or II\] breast cancer treated with surgery and radiation +/- hormones \[without adjuvant chemotherapy\], non-melanoma skin cancer, fully excised melanoma in situ \[stage 0\], curatively treated localized prostate cancer, and cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on Papanicolaou test \[PAP smear\])
5. Known cerebral/meningeal disease (HL or any other etiology), including signs or symptoms of progressive multifocal leukoencephalopathy (PML)
6. Any active systemic viral, bacterial, or fungal infection requiring treatment with antimicrobial therapy within 1 week prior to first dose
7. Known or suspected hepatitis B infection, or known or suspected active hepatitis C infection Known human immunodeficiency virus (HIV) positive
8. Patients with a known hypersensitivity to recombinant proteins, murine proteins, or to any excipient contained in the drug formulation of brentuximab vedotin
9. Patients with dementia or an altered mental state that would preclude the understanding and rendering of informed consent
10. Symptomatic neurologic disease compromising normal activities of daily living or requiring medications
11. Any sensory or motor peripheral neuropathy greater than or equal to 2
12. Known history of any of the following cardiovascular conditions;

    1. Myocardial infarction within 2 years of enrollment
    2. New York Heart Association (NYHA) Class III or IV heart failure
    3. Evidence of uncontrolled cardiovascular conditions, including cardiac arrhythmias,congestive heart failure (CHF), angina, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities