A Study of Brentuximab Vedotin in Patients With Hodgkin Lymphoma Unsuitable for Chemotherapy Due to Age, Frailty or Co-morbidity

An early phase II, single arm, two stage study, to investigate the level of activity, duration of response and tolerability of brentuximab vedotin (SGN-35), as a single agent, utilising a response adapted approach, in older, frailer or co-morbid patients with previously untreated Hodgkin lymphoma.

Opened Feb 2014 and will recruit over 18 months. Duration of treatment will be dependent on the patients' response (see schema below) with a maximum of 16 cycles over 48 weeks.

At the end of treatment patients will be assessed clinically at 3 months intervals and by CT scan at 15, 18, 24 and 36 months. For those still alive and disease free after 2 years, follow-up will be according to local practice.

Stage 1 will recruit 20 patients. If at least patients 8 respond after the initial 4 cycles of SGN-35 a further 10 patients will be recruited to stage 2.

In all cases brentuximab vedotin will be administered at an initial dose of 1.8 mg/kg every 3 weeks as a 30-minute outpatient i.v. infusion.

After baseline staging (including PET and CT scans (PET0 + CT0), performed on PET scanners approved for the purpose by The PET Imaging Centre at St Thomas'/Guy's), all eligible and consenting patients will receive an initial 4 cycles of brentuximab vedotin following which response and continuation of brentuximab vedotin will be assessed by PET (PET4) in the first instance. Patients achieving CMR (Deauville score 1-3) will continue treatment. Patients achieving PMR (Deauville score 4,5 with uptake less than baseline) will also continue treatment. Patients achieving NMR (Deauville score 4,5 with no change in uptake from baseline) or PMD (Deauville score 4,5 with increased intensity of uptake compared to baseline and/or new lesions consistent with lymphoma) will stop brentuximab vedotin and be considered for alternative therapy.

CT4 will be performed for future comparison with CT8, CT12 and CT 16 (to exclude Progressive Disease (PD) and to correlate metabolic and radiological responses) and to inform continued treatment. Patients not achieving Deauville score 1-3 at PET 4 will also have a PET scan at completion of treatment (after 16 cycles or earlier if brentuximab vedotin discontinued for reasons other than PD)

In addition an exploratory PET scan will be performed after 2 cycles of brentuximab vedotin (PET2); investigators will be blinded to the results of PET2 which will not influence patient management in any way. All PET scans will be centrally reviewed for QA purposes by The PET Imaging Centre at St Thomas'/Guy's, under the supervision of Sally Barrington and Mike O'Doherty, using the framework developed for the recently completed RAPID and RATHL trials. CT scans after 4 cycles and at the end of treatment may also be reviewed.

After the initial 4 cycles of brentuximab vedotin, subsequent treatment will be response adapted according to PET scan result the following schedule:

* Those with a Complete Metabolic Response (CMR, Deauville Score 1, 2 or 3) at PET 4 will receive up to 12 additional cycles of brentuximab vedotin (maximum of 16 cycles) depending on no evidence of PD by a CT scan performed after each group of 4 cycles of brentuximab vedotin.
* Patients with a Partial Metabolic Response (PMR) at PET4 will receive up to 12 additional cycles of brentuximab vedotin (maximum of 16 cycles) depending on no evidence of PD on a CT scan performed after each group of 4 cycles of brentuximab vedotin.
* Patients with No Metabolic Response (NMR) will stop brentuximab vedotin and be considered for alternative therapy.
* Patients with progressive disease at any time as determined by either CT or PET scan performed after each group of 4 cycles of brentuximab vedotin or in response to clinical concerns will stop study treatment and receive subsequent therapy at investigator discretion. Clinical concerns over PD should be confirmed by either a CT or PET scan.
* Patients who come off treatment with brentuximab vedotin for any other reason (toxicity, patient decision, investigator advice) should have a CT scan performed for response assessment. In addition patients with Partial Metabolic Response at PET 4 should also have a PET scan performed.

All patients who have not progressed irrespective of how many cycles of brentuximab vedotin received will be clinically assessed every 3 months and have a CT scan at months 3, 6, 9, 12. These scan may take place during therapy. During follow-up CT scans will be performed 15, 18, 24 and 36 months from the start of treatment. For those still alive and disease-free after 3 years following start of treatment, follow-up will be according to local practice but data recorded must include date of progressive disease, type of any subsequent therapies, date and cause of death.

For patients who progress at any time, follow-up will be according to local practice but data must be recorded for 5 years form the start of treatment and must include date of progressive disease, type of any subsequent therapies, date and cause of death.

Eligibility Criteria:
Inclusion Criteria:

1. Histologically confirmed CD30 positive classical Hodgkin lymphoma
2. No previous treatment for classical Hodgkin lymphoma
3. Aged ≥ 16 years
4. Stages II (with B symptoms, extranodal disease, bulky disease, ≥3 sites of nodal involvement, fewer than 3 sites of nodal involvement but unsuitable for radiotherapy because of anatomical distribution or ESR ≥50 mm/h), III and IV classical Hodgkin lymphoma
5. Any of the following:

   At any age and with ECOG score of 0, 1, 2 or 3, for whom standard chemotherapy considered inappropriate because:
   * Impaired cardiac function defined either by an ejection fraction of \< 50% assessed by echocardiogram or nuclear medicine scan (MUGA)
   * Left ventricular ejection fraction ≥50% measured by echocardiography or MUGA but in the presence of significant co-morbidities or cardiac risk factors such as diabetes mellitus, hypertension, peripheral vascular disease, ischaemic heart disease, previous myocardial infarction, obesity, stroke or transient ischaemic attacks (TIA) that make anthracycline-containing chemotherapy inadvisable as determined by the investigator.
   * Heart failure clinically determined by the presence of New York Heart Association (NYHA) heart failure grade II and III due to a cause other than Hodgkin Lymphoma
   * Impaired respiratory function with DLCO and/or FVC/FEV1 ratio \<75% of predicted due to a cause other than Hodgkin lymphoma

   For patients aged 60 years or older,
   * an ECOG score of 1, 2 or 3 for any reason, before the start of permitted steroids (see section 7.9) and considered unsuitable for treatment with standard chemotherapy by the investigator

   All co-morbidities must be documented on the baseline form and the CIRS-G score (if 60 years or older) recorded.
6. FDG avid disease - proven by PET scan
7. Measurable disease with at least one lesion measuring \>1.5 cm in long axis diameter (for nodal lesions) or \>1.0cm in long axis diameter (for extra-nodal lesions)
8. Written informed consent
9. Able to comply with requirements of the protocol (including PET scans)
10. Agree and be able to use adequate contraception if required

Exclusion Criteria:

1. Nodular lymphocyte predominant Hodgkin lymphoma
2. Grade 2 or worse peripheral neuropathy
3. Haemoglobin \<90 g/L (transfusion allowed)
4. Unsupported neutrophil count \<1.0 x 109/l and platelet count \<100 x 109/l unless due to bone marrow infiltration by Hodgkin lymphoma demonstrated by trephine biopsy
5. Serum bilirubin ≥1.5 times upper limit normal unless due to Hodgkin lymphoma or Gilbert's syndrome
6. Creatinine clearance \<30 ml/min (calculated by the modified Cockroft-Gault formula, see appendix) unless due to Hodgkin lymphoma. Patients with an eGFR \<30 ml/min but a measured GFR by another method (e.g. EDTA) of 30ml/min or greater would be eligible.
7. Pregnant or lactating women
8. Any other cancer diagnosis within the last 24 months - except for:

   * Appropriately treated superficial melanoma, basal cell carcinoma and squamous cell carcinoma of the skin
   * Appropriately treated cervical intra-epithelial neoplasia
   * In situ or organ confined prostate cancer not currently requiring therapy

   Previous cancers treated with curative intent and with no evidence of recurrence following a minimum of at least 2 years of follow-up are permitted.
9. The use of other investigational or anti-neoplastic agents within the previous 6 weeks or during the trial.
10. Known to be HIV, Hep B positive (Hep B Core antibody positive allows inclusion providing surface / core antigen both negative) or Hep C positive (Hep C antibody positive allows inclusion providing PCR for viral RNA is negative).
11. Known hypersensitivity to recombinant proteins, murine proteins, or to any excipient contained in the drug formulation of brentuximab vedotin.
12. Known cerebral or meningeal involvement by Hodgkin lymphoma
13. Symptoms or signs of progressive multifocal leukoencephalopathy (PML)
14. Any active systemic viral, bacterial, or fungal infection requiring intravenous antimicrobials within 2 weeks prior to registration
15. Evidence of current uncontrolled cardiovascular conditions, including unstable angina and NYHA grade IV heart failure
16. ECOG 4 at registration