Placebo‐associated remissions in a multicentre, randomized, double‐blind trial of interferon γ‐1b for the treatment of metastatic renal cell carcinoma

Elhilali, Mostafa; Gleave, M.E.; Fradet, Yves; Davis, Ian D.; Venner, Peter; Saad, Fred; Klotz, Laurence; Moore, Ronald B.; Ernst, Scott; Paton, Virginia

doi:10.1046/j.1464-410x.2000.00880.x

Cited by 50 publications

(22 citation statements)

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“…Approval decisions have often been bolstered by quality-of-life outcomes, a type of evidence that is not generally available for phase I oncology studies. 16 Further complicating the reliance on phase I meta-analyses, open-label phase I studies cannot exclude natural regression [17][18][19][20] or radiography error. One systematic review of cancer trials found that patients in placebo arms showed a 2.4% response rate.…”

Section: Evidencementioning

confidence: 99%

Is Participation in Cancer Phase I Trials Really Therapeutic?

Kimmelman

2017

JCO

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Phase I trials are a key step in developing anticancer treatments. But because they administer unproven drugs to populations with life-threatening disease, their design and ethics are often debated. [1][2][3][4] In 1995, ASCO issued a policy declaring the importance of phase I studies as a treatment modality for patients with cancer who have advanced disease. ASCO revisited its policy in 2014. 5 The new policy amplifies the earlier position, reasserting two closely connected claims: first, that phase I cancer studies have therapeutic intent, and second, that they potentially "provide patients [who enroll with clinical benefit." 5(p1) In this article, I reinforce the first assertion and qualify the second. The therapeutic intent of many phase I cancer studies is attested to by the fact that most studies measure disease response, and many use designs aimed at maximizing clinical benefit. However, intent alone does not underwrite an actual therapeutic claim. The assertion that phase I trials offer a vehicle for pursuing cancer treatment (the "therapeutic position") rests on weak evidence and has counterproductive implications for human protection. It also erodes the ability of oncologists to rigorously evaluate new treatments and support evidence-based practice. Instead I propose a different view-the "research position"-that stresses the investigational orientation of phase I trials while accommodating exceptional cases and the therapeutic yearnings of patients and their caregivers. I close by suggesting how groups such as ASCO might refine their recommendations. EvidenceThe kernel of the therapeutic position expressed by ASCO is that investigators can and should present phase I trial participation as providing "the prospect of a direct medical benefit." 5(p2) Because direct benefit relates to the pharmacologic action of a drug, and because benefit in medicine is always measured against how patients would be treated otherwise, the therapeutic position is equivalent to saying that the risk/benefit for receiving experimental drugs in phase I trials is consistent with and possibly superior to standard of care.Proponents of this view draw on several streams of evidence. First, meta-analyses show objective response rates (ORRs) in the neighborhood of 5% and fatal toxicities of approximately 0.5% for monotherapy studies. [6][7][8] Proponents argue that these response rates

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Section: Evidencementioning

confidence: 99%

Is Participation in Cancer Phase I Trials Really Therapeutic?

Kimmelman

2017

JCO

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“…Evidence that clear-cell RCC is an immunogenic tumour includes observed spontaneous tumour regression in 1 -4% of patients (Elhilali et al, 2000), the presence of lymphocytic infiltrates in tumour, and responsiveness of RCC to cytokine therapy. A number of studies have been reported demonstrating the ability of interferon alpha and interleukin-2 (IL-2) to engender a tumour response (Fyfe et al, 1995;Pyrhonen et al, 1999;MRCRC Collaborators, 1999;Yang et al, 2003b;McDermott et al, 2005).…”

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confidence: 99%

Vaccination of metastatic renal cell carcinoma patients with autologous tumour-derived vitespen vaccine: clinical findings

et al. 2008

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The aim of this study was to evaluate the clinical efficacy as determined by time to progression and response rate (RR) of autologous vitespen (formerly HSPPC-96; Oncophage, Antigenics Inc., New York, NY, USA) with and without interleukin-2 (IL-2; Proleukin: Chiron, Emoryville, CA, USA) in stage IV metastatic renal cell carcinoma (RCC) patients undergoing nephrectomy. Eighty-four patients were enrolled on study, and then underwent nephrectomy and harvest of tumour tissue for use in autologous vaccine manufacture. Initial treatment schedule started approximately 4 weeks after surgery and consisted of six injections: once weekly for 4 weeks, then two injections biweekly (vaccines administered at weeks 1, 2, 3, 4, 6, 8), followed by restaging at or around week 10. Patients who had stable or responsive disease continued to receive vaccine, with four more vaccinations biweekly (at weeks 10, 12, 14, 16). Patients who had progressive disease at week-10 evaluation received four consecutive 5-day-per-week courses of 11 × 10 6 U of IL-2 subcutaneously (weeks 10, 11, 12, 13), with four doses of vitespen at 2-week intervals (at weeks 10, 12, 14, 16). At the next evaluation (week 18), patients with a complete response received two further cycles of vitespen (with IL-2 if also received during prior cycle) or until vaccine supply was exhausted. Patients with stable disease or partial response repeated their prior cycle of therapy. Disease progressors who had not yet received IL-2 began IL-2 treatment, and progressors who had already received IL-2 came off study. Of 60 evaluable patients, 2 demonstrated complete response (CR), 2 showed partial response (PR), 7 showed stable disease, and 33 patients progressed. Sixteen patients had unconfirmed stable disease. Two patients who progressed on vaccine alone experienced disease stabilisation when IL-2 was added. Treatment with vitespen did not result in a discernable benefit in the majority of patients with metastatic RCC treated in this study. Use in combination with immunoregulatory agents may enhance the efficacy of vitespen.

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“…Whereas several adult solid cancers have been documented to occasionally regress in the absence of therapy, melanoma and renal cell carcinoma (renal cell carcinoma) compose the significant majority of such observations (12). Metastatic renal cell carcinoma may regress partially or completely in up to 6% to 7% of cases and durations may be prolonged (13,14). Such responses to placebo have led to the suggestion that a minimum response rate of 18% be required of an agent in phase II studies before proceeding to phase III studies (14).…”

mentioning

confidence: 99%

“…Metastatic renal cell carcinoma may regress partially or completely in up to 6% to 7% of cases and durations may be prolonged (13,14). Such responses to placebo have led to the suggestion that a minimum response rate of 18% be required of an agent in phase II studies before proceeding to phase III studies (14). Pathologic assessment of melanoma specimens suggests some degree of remission in 10% to 36% of cases (15).…”

mentioning

confidence: 99%

Objective Responses in Patients with Malignant Melanoma or Renal Cell Cancer in Early Clinical Studies Do Not Predict Regulatory Approval

Goffin

Baral

et al. 2005

Clinical Cancer Research

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Purpose: Tumor responses in early-phase trials are used to determine whether new agents warrant further study. Given that spontaneous regressions are observed in melanoma and renal cell carcinoma, this study assessed whether tumor responses, particularly in these two tumor types, predict for future regulatory drug approval. Experimental Design: The literature was reviewed to assess tumor response rates to cytotoxic agents in phase I and II trials in the following solid tumors: melanoma, renal cell carcinoma, nonŝ mall-cell lung cancer, breast cancer, ovarian cancer, colorectal cancer, and other solid tumors.Response rates were categorized and the relationship of these categories to the end point of regulatory drug approval was determined.Results: Fifty-eight drugs were assessed in 100 phase I trials, and 46 of these drugs were also studied in 499 phase II trials. Higher overall response rates in both phase I trials (P = 0.03) and phase II trials (P < 0.0001) were predictive of regulatory approval. However, response in melanoma or renal cell carcinoma was not predictive for either phase I or phase II studies.Conclusions: For cytotoxic agents, although overall objective response rates reliably predict subsequent marketing approval, isolated responses in melanoma and renal cell carcinoma are not predictive.Contemporary drug development in oncology is extremely resource intensive. Only one in ten drugs that enter the clinic is eventually approved for use (1) and the dollar cost to bring a drug to market can approach U.S. $800 million (2). The human cost of late-phase development of inactive therapeutics is also considerable, and includes toxicity suffered by research subjects, unrealistic hope generated by seemingly promising new agents, and the wasted accrual of the limited pool of patients who are eligible for trials. Hundreds, or even thousands, of patients may be exposed to a new agent only to eventually determine that it does not provide clinical benefit, sometimes after completion of multiple phase III trials. Objective tumor response remains the most commonly used end point or surrogate of drug efficacy, and tumor response has been shown to correlate with survival (3 -6). In lung cancer, for example, a response rate of 15% is usually considered sufficient to merit further investigation of an agent (7).The decision whether to continue the development of a new therapeutic based on the results of early clinical trials (phase I or II) may be challenging, and is based on an evaluation of the therapeutic index. Whereas new therapeutics can be developed despite manageable toxicities, a critical consideration is the antitumor activity of the agent. Some clues can be gleaned from preclinical studies. have shown that preclinical data may predict for tumor responsiveness to cytotoxic agents in phase II studies. Measures of tumor control in in vitro human tumor cell line models, murine xenograft models, and murine tumor allograft models were compared with the phase II response rates in studies of non -small-cel...

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Placebo‐associated remissions in a multicentre, randomized, double‐blind trial of interferon γ‐1b for the treatment of metastatic renal cell carcinoma

Cited by 50 publications

References 32 publications

Is Participation in Cancer Phase I Trials Really Therapeutic?

Is Participation in Cancer Phase I Trials Really Therapeutic?

Vaccination of metastatic renal cell carcinoma patients with autologous tumour-derived vitespen vaccine: clinical findings

Objective Responses in Patients with Malignant Melanoma or Renal Cell Cancer in Early Clinical Studies Do Not Predict Regulatory Approval

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